Search

Introduction: Cerebral small vessel disease (cSVD) is a growing epidemic that affects brain health and cognition. Therefore, a more profound understanding of the interplay between cSVD, brain atrophy, and cognition in healthy aging is of great importance. In this study, we examined the association between white matter hyperintensities (WMH) volume, number of lacunes, entorhinal cortex (EC) thickness, and declarative memory in cognitively healthy older adults over a seven-year period, controlling for possible confounding factors. Because there is no cure for cSVD to date, the neuroprotective potential of an active lifestyle has been suggested. Supporting evidence, however, is scarce. Therefore, a second objective of this study is to examine the relationship between leisure activities, cSVD, EC thickness, and declarative memory. Methods: We used a longitudinal dataset, which consisted of five measurement time points of structural MRI and psychometric cognitive ability and survey data, collected from a sample of healthy older adults (baseline N = 231, age range: 64–87 years, age M = 70.8 years), to investigate associations between cSVD MRI markers, EC thickness and verbal and figural memory performance. Further, we computed physical, social, and cognitive leisure activity scores from survey-based assessments and examined their associations with brain structure and declarative memory. To provide more accurate estimates of the trajectories and cross-domain correlations, we applied latent growth curve models controlling for potential confounders. Results: Less age-related thinning of the right (β = 0.92, p

Abstract Altered intrinsic brain connectivity of patients with anorexia nervosa has been observed in the acute phase of the disorder, but it remains unclear to what extent these alterations recover during weight normalization. In this study, we used functional imaging data from three time points to probe longitudinal changes in intrinsic connectivity patterns in patients with severe anorexia nervosa (BMI ≤ 15.5 kg/m2) over the course of weight normalization. At three distinct stages of inpatient treatment, we examined resting-state functional connectivity in 27 women with severe anorexia nervosa and 40 closely matched healthy controls. Using network-based statistics and graph-theoretic measures, we examined differences in global network strength, subnetworks with altered intrinsic connectivity, and global network topology. Patients with severe anorexia nervosa showed weakened intrinsic connectivity and altered network topology which did not recover during treatment. The persistent disruption of brain networks suggests sustained alterations of information processing in weight-recovered severe anorexia nervosa.

Custom proteases find applications as therapeutics, in research and in biotechnological applications. Here, the authors establish a protease selection system based on bacterial alpha-2-macroglobulin protease inhibitors and evolve staphylococcal proteases for increased activity and altered specificity.

Abstract The inotropic effects of glucagon have been recognized for many years, but it has remained unclear whether glucagon signaling is beneficial to cardiac function. We evaluated the effects of glucagon alone and in combination with the glucagon‐like peptide 1 (GLP‐1) receptor agonist exenatide in the isolated perfused rat heart. The isolated perfused rat heart was used to investigate the initial inotropic and chronotropic effects of glucagon and exenatide during aerobic perfusion, and recovery of contractile function following ischaemia/reperfusion. Glucagon, but not exenatide, elicited an acute chronotropic and inotropic response during aerobic perfusion of the rat heart. Compared with control, glucagon improved recovery of left ventricular developed pressure (LVDP) by 33% (p

Summary: Background: Psilocybin has been suggested as a novel, rapid-acting treatment for depression. Two consecutive doses have been shown to markedly decrease symptom severity in an open-label setting or when compared to a waiting list group. To date, to our knowledge, no other trial compared a single, moderate dose of psilocybin to a placebo condition. Methods: In this double-blind, randomised clinical trial, 52 participants diagnosed with major depressive disorder and no unstable somatic conditions were allocated to receive either a single, moderate dose (0.215 mg/kg body weight) of psilocybin or placebo in conjunction with psychological support. MADRS and BDI scores were assessed to estimate depression severity, while changes from baseline to 14 days after the intervention were defined as primary endpoints. The trial took place between April 11th, 2019 and October 12th, 2021 at the psychiatric university hospital in Zürich, Switzerland and was registered with clinicaltrials.gov (NCT03715127). Findings: The psilocybin condition showed an absolute decrease in symptom severity of −13.0 points compared to baseline and were significantly larger than those in the placebo condition (95% CI −15.0 to −1.3; Cohens' d = 0.97; P = 0.0011; MADRS) and −13.2 points (95% CI; −13.4 to −1.3; Cohens’ d = 0.67; P = 0.019; BDI) 14 days after the intervention. 14/26 (54%) participants met the MADRS remission criteria in the psilocybin condition. Interpretation: These results suggest that a single, moderate dose of psilocybin significantly reduces depressive symptoms compared to a placebo condition for at least two weeks. No serious adverse events were recorded. Larger, multi-centric trials with longer follow-up periods are needed to inform further optimisation of this novel treatment paradigm. Funding: The study was funded by the Swiss National Science Foundation, Crowdfunding, the Swiss Neuromatrix Foundation, and the Heffter Research Institute.

Abstract Cardiac alterations are frequently observed after acute neurological disorders. Takotsubo syndrome (TTS) represents an acute heart failure syndrome and is increasingly recognized as part of the spectrum of cardiac complications observed after neurological disorders. A systematic investigation of TTS patients with neurological disorders has not been conducted yet. The aim of the study was to expand insights regarding neurological disease entities triggering TTS and to investigate the clinical profile and outcomes of TTS patients after primary neurological disorders. The International Takotsubo Registry is an observational multicenter collaborative effort of 45 centers in 14 countries (ClinicalTrials.gov, identifier NCT01947621). All patients in the registry fulfilled International Takotsubo Diagnostic Criteria. For the present study, patients were included if complete information on acute neurological disorders were available. 2402 patients in whom complete information on acute neurological status were available were analyzed. In 161 patients (6.7%) an acute neurological disorder was identified as the preceding triggering factor. The most common neurological disorders were seizures, intracranial hemorrhage, and ischemic stroke. Time from neurological symptoms to TTS diagnosis was ≤ 2 days in 87.3% of cases. TTS patients with neurological disorders were younger, had a lower female predominance, fewer cardiac symptoms, lower left ventricular ejection fraction, and higher levels of cardiac biomarkers. TTS patients with neurological disorders had a 3.2-fold increased odds of in-hospital mortality compared to TTS patients without neurological disorders. In this large-scale study, 1 out of 15 TTS patients had an acute neurological condition as the underlying triggering factor. Our data emphasize that a wide spectrum of neurological diseases ranging from benign to life-threatening encompass TTS. The high rates of adverse events highlight the need for clinical awareness.

Cross-sectional studies have consistently identified age-associated alterations in default mode network (DMN) functional connectivity (FC). Yet, research on longitudinal trajectories of FC changes of the DMN in healthy aging is less conclusive.For the present study, we used a resting state functional MRI dataset drawn from the Longitudinal Healthy Aging Brain Database Project (LHAB) collected in 5 occasions over a course of 7 years (baseline N = 232, age range: 64–87 y, mean age = 70.85 y). FC strength changes within the DMN and its regions were investigated using a network-based statistical method suitable for the analysis of longitudinal data. The average DMN FC strength remained stable, however, various DMN components showed differential age- and time-related effects. Our results revealed a complex pattern of longitudinal change seen as decreases and increases of FC strength encompassing the majority of DMN regions, while age-related effects were negative and present in select brain areas. These findings testify to the growing importance of longitudinal studies using more sophisticated fine-grained tools needed to highlight the complexity of the functional reorganization of DMN with healthy aging.

ObjectivePhase-oriented trauma treatment is efficacious in the treatment of complex trauma and dissociative disorder patients. However, the neural correlates of this therapeutic effect are not yet well-understood. In the current study we investigated whether patients show a strengthening in functional network connectivity in the delta frequency band (1–3.5 Hz) over the course of phase-oriented inpatient trauma treatment while they performed an emotion regulation task. Further, we examined whether neural changes were associated with symptom reduction and improvement in emotion regulation skills.MethodsBefore and after 8 weeks of treatment, electroencephalography (EEG) was acquired in patients (n = 28) with a complex posttraumatic stress disorder (cPTSD) or complex dissociative disorder (CDD). They also completed clinical and emotion regulation questionnaires. To delimit data variability, patients participated as one dissociative part that is referred to as Apparently Normal Part (ANP). Patients' data were compared to a matched healthy control croup (n = 38), also measured twice.ResultsPrior to treatment, functional connectivity was significantly lower in patients compared to controls during cognitive reappraisal of unpleasant pictures and passive viewing of unpleasant and neutral pictures. These hypoconnected networks largely overlapped with networks typically activated during the recall of (emotional) autobiographical memories. Functional connectivity strength within these networks significantly increased following treatment and was comparable to controls. Patients showed symptom reduction across various clinical domains and improvement in the use of cognitive reappraisal as emotion regulation strategy. Treatment-related network normalizations were not related to changes in questionnaire data.ConclusionPhase-oriented treatment may strengthen connections between regions that are activated during autobiographical recall. These findings encourage further investigation of this circuitry as a therapeutic target in cPTSD and CDD patients.Clinial trial registrationwww.ClinicalTrials.gov, identifier: NCT02459340, https://www.kofam.ch/de/studienportal/suche/149284/studie/26681.

Studies investigating the structure of the amygdala in relation to dissociation in psychiatric disorders are limited and have reported normal or preserved, increased or decreased global volumes. Thus, a more detailed investigation of the amygdala is warranted. Amygdala global and subregional volumes were compared between individuals with dissociative identity disorder (DID: n = 32) and healthy controls (n = 42). Analyses of covariance did not show volumetric differences between the DID and control groups. Although several unknowns make it challenging to interpret our findings, we propose that the finding of normal amygdala volume is a genuine finding because other studies using this data-set have presented robust morphological aberrations in relation to the diagnosis of DID.

Abstract Background Esophagogastric adenocarcinoma (EGA) currently represents a main cause of cancer related death. Despite an intensified treatment for locally advanced or metastatic EGA with a doublet chemotherapy consisting of a platinum compound and a fluoropyrimidine in combination with trastuzumab for HER2-positive disease or in selected cases with docetaxel, survival remains poor. Recently, immune-oncology based strategies relevantly improved the treatment of different solid tumors and showed some promise in late or later stage trials in EGA. Notably, the combination of immunotherapy with trastuzumab to enhance anti-tumor immunity through activation of innate and adaptive immunity was beneficial in preclinical studies or clinical studies in breast cancer. Methods The INTEGA study is an open-label, randomized, multicenter, exploratory phase II trial designed to assess clinical performance, safety and tolerability of ipilimumab or 5-FU/folinic acid and oxaliplatin (FOLFOX) in combination with nivolumab and trastuzumab in patients with previously untreated HER2-positive, locally advanced or metastatic EGA. The primary objective is to determine the clinical performance of ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in terms of overall survival. Secondary objectives are safety and tolerability, efficacy in terms of progression-free survival and objective response rate and blood-based signatures (e.g. immune response or suppression of anti-HER2 resistance) that may correlate with treatment response. Discussion Recent evidence from the phase II NCT02954536 study (oxaliplatin, capecitabine, trastuzumab and pembrolizumab) suggests the clinical feasibility of combining chemotherapy, trastuzumab and checkpoint inhibition in EGA. However, evidence for a chemotherapy-free regimen is also mounting in HER2-positive disease (NCT02689284) i.e. margetuximab and Pembrolizumab. Both studies excelled with high overall response rates and manageable toxicities. The INTEGA study aims to comparatively assess these results and select a promising new 1st line regimen which then needs to be confirmed in a randomized phase III trial. Further, the translational part of the study might help to better stratify patients and tailor treatment of either arm. Trial registration NCT03409848 24.01.2018.

This study characterizes a large sample of adults with attention-deficit/hyperactivity disorder (ADHD) and healthy controls regarding their task performance and neurophysiology; cross-sectionally and longitudinally. Self-reported symptoms, behavioral measures, and event-related potentials from a classical cued Go/NoGo task were used to outline the symptom burden, executive function deficits and neurophysiological features, and the associations between these domains. The study participants (N = 210 ADHD, N = 158 controls, age: 18–62 years) were assessed five (ADHD) or three (controls) times over two years. We describe cross-sectional and longitudinal group differences, and associations between symptom burden, and behavioral and event-related potential (ERP) components variables by latent growth curve models, including random slopes and intercepts. The ADHD group showed increased reaction time variability, increased commission and omission errors, and attenuated cueP3, CNV, N2d, and P3d amplitudes. We observed a decrease in self-reported symptoms in the ADHD group over the two years. The behavioral measures (reaction time variability, number of omission, and commission errors) did not change over time, whereas the cueP3, P3d, and N2d amplitude attenuated in both groups. There was no evidence for a robust association between symptom burden and behavioral or ERP measures. The changes in the ERP components with stable task performance, potentially indicate more efficient neuronal processing over the two years. Whether the lack of association between symptom burden and behavioral or ERP measures might be due to the low reliability of the ADHD assessment criteria, or the inappropriateness of the objective measures cannot be inferred.

Background: Given the present demographic shift towards an aging society, there is an increased need to investigate the brain’s functional connectivity in the context of aging. Trauma exposure and post-traumatic stress disorder (PTSD) symptoms are factors known to impact healthy aging and have been reported to be associated with functional connectivity differences. In the present study, we examined and compared differences in within-Default Mode Network (DMN), within-Salience Network (SN) and between DMN-SN functional connectivity, between trauma-exposed individuals with and without PTSD symptoms as well as non-traumatized individuals in a non-clininical older adult sample. METHODS: Resting state functional MRI and behavioral data is taken from the Longitudinal Healthy Aging Brain Database Project (LHAB). For the present analysis, participants who completed the questionnaires on trauma exposure and PTSD symptoms (N = 110 individuals of which n = 50 individuals reported previous trauma exposure and n = 25 individuals reported PTSD symptoms; mean age = 70.55 years, SD = 4.82) were included. RESULTS: The reporting of PTSD symptoms relative to no symptoms was associated with lower within-DMN connectivity, while on a trend level trauma-exposed individuals showed higher within-SN connectivity compared to non-trauma exposed individuals. Consistent with existing models of healthy aging, between DMN-SN functional connectivity showed an increase across time in older age. CONCLUSION: Present results suggest that alterations in within-DMN and within-SN functional connectivity also occur in non-treatment seeking older adult populations with trauma exposure and in association with PTSD symptoms. These changes manifest, alongside altered between DMN-SN functional connectivity, in older age supposedly independent of aging-related functional desegregation.

Magnetic Resonance Imaging (MRI) studies have shown that cortical volume declines with age. Although volume is a multiplicative measure consisting of thickness and area, few studies have focused on both its components. Information on decline variability and associations between person-specific changes of different brain metrics, brain regions, and cognition is sparse. In addition, the estimates have often been biased by the measurement error, because three repeated measures are minimally required to separate the measurement error from person-specific changes. With a sample size of N = 231, five repeated measures, and an observational time span of seven years, this study explores the associations between changes of different brain metrics, brain regions, and cognitive abilities in aging.Person-specific changes were obtained by latent growth curve models using Bayesian estimation. Our data indicate that both thickness and area are important contributors to volumetric changes. In most brain regions, area clearly declined on average over the years, while thickness showed only little decline. However, there was also substantial variation around the average slope in thickness and area. The correlation pattern of changes in thickness between brain regions was strong and largely homogenous. The pattern for changes in area was similar but weaker, indicating that factors affecting area may be more region-specific. Changes in thickness and volume were substantially correlated with changes in cognition. In some brain regions, changes in area were also related to changes in cognition. Overall, studying the associations between the trajectories of brain regions in different brain metrics provides insights into the regional heterogeneity of structural changes. Significance statement: Many studies have described volumetric brain changes in aging. Few studies have focused on both its individual components: area and thickness. Longitudinal studies with three or more time points are highly needed, because they provide more precise average change estimates and, more importantly, allow us to quantify the associations between changes in the different brain metrics, brain regions, and other variables (e.g. cognitive abilities). Studying these associations is important because they can provide information regarding possible underlying factors of these changes. Our study, with a large sample size, five repeated measures, and an observational time span of seven years, provides new insights about the associations between person-specific changes in thickness, area, volume, and cognitive abilities.

Abstract Introduction Recent research suggests that traumatized patients are characterized by disrupted resting‐state functional connectivity. We examined whether neural networks involved in resting‐state change over the course of a phase‐oriented inpatient treatment for complex traumatized and dissociative disorder patients. We also investigated associations between these network alterations and clinical symptoms and emotion regulation skills. Methods Pre‐ and post‐treatment, electroencephalography (EEG) was recorded during resting‐state in patients (n = 23) with a complex dissociative disorder (CDD) or complex posttraumatic stress disorder (cPTSD). Patients also completed clinical and emotion regulation questionnaires. To reduce variance in the collected data, patients were exclusively tested as one prototypical dissociative part referred to as Apparently Normal Part (ANP). Functional network connectivity was examined and compared with a matched healthy control group (n = 37), also measured twice. Results Prior to treatment and compared with controls, patients had a significantly lower functional connectivity strength within eyes‐open and eyes‐closed resting‐state networks in the theta and alpha frequency band. Following treatment, functional connectivity strength within these networks was comparable to the control group and comprised areas belonging to the default mode network (DMN) and prefrontal as well as anterior cingulate control regions. Treatment‐related network normalizations in the theta frequency band were associated with a self‐reported increase in the use of cognitive reappraisal strategies and reduction in emotion regulation difficulties. Conclusion Phase‐oriented trauma treatment can strengthen resting‐state network connectivity and can increase the capacity of complex traumatized and dissociative patients as ANP to handle emotional challenges effectively.

BackgroundWhile it is well-known that deficits in motor performance and brain structural connectivity occur in the course of healthy aging, it is still unclear if and how these changes are related to each other. While some cross-sectional studies suggest that white matter (WM) microstructure is positively associated with motor function in healthy older adults, more evidence is needed. Moreover, longitudinal data is required to estimate whether similar associations can be found between trajectories of change in WM microstructure and motor function. The current study addresses this gap by investigating age-associations and longitudinal changes in WM microstructure and motor function, and the cross-sectional (level-level) and longitudinal (level-change, change-change) association between these two domains.MethodWe used multiple-occasion data (covering 4 years) from a large sample (N = 231) of healthy older adults from the Longitudinal Healthy Aging Brain (LHAB) database. To measure WM microstructure, we used diffusion-weighted imaging data to compute mean FA in three selected WM tracts [forceps minor (FMIN); superior longitudinal fasciculus (SLF); corticospinal tract (CST)]. Motor function was measured via two motor speed tests (grooved pegboard, finger tapping) and one motor strength test (grip force test), separately for the left and the right hand. The statistical analysis was conducted with longitudinal growth curve models in the structural equation modeling framework.ResultsThe results revealed longitudinal decline and negative cross-sectional age-associations for mean WM FA in the FMIN and SLF, and for motor function in all tests, with a higher vulnerability for left than right hand motor performance. Regarding cross-domain associations, we found a significant positive level-level correlation among mean WM FA in the FMIN with motor speed. Mean FA in SLF and CST was not correlated with motor performance measures, and none of the level-change or change-change associations were significant. Overall, our results (a) provide important insights into aging-related changes of fine motor abilities and FA in selected white matter tracts associated with motor control, (b) support previous cross-sectional work showing that neural control of movement in older adults also involves brain structures outside the core motor system and (c) align with the idea that, in healthy aging, compensatory mechanisms may be in place and longer time delays may be needed to reveal level-change or change-change associations.

Abstract Introduction Although the interest is growing in topical low-dose atropine to control myopia in schoolchildren worldwide, its use in children of European ancestry remains controversial and solid evidence is sparse. The Oxford Centre for Evidence Based Medicine (OCEBM) classifies the evidence for this therapy as level I for East Asian populations, but only level IV in non-Asian populations. Methods Fifty-six children, aged a median of 11 years (range 6–17), were analysed after 12 months of topical treatment with 0.01% preservative-free atropine in both eyes at bedtime every day. Efficacy was assessed during treatment every 6 months. In a subset of 20 patients, treatment of the second eye was delayed by 1 day to enable a controlled safety assessment of side effects such as pupil dilation, hypoaccommodation, and near vision reduction. Results Prior to treatment, the mean myopic progression was estimated as 1.05 D/year; after 12 months of treatment with 0.01% atropine, it was 0.40 D/year (p

Abstract Background Health care workers have an increased risk of being infected with Methicillin-resistant Staphylococcus aureus (MRSA), though little information is available about how prevalent (dormant) MRSA colonization is among health care workers. The aim of this study was to estimate the prevalence and predictors of MRSA carriage in a non-outbreak setting in a university hospital in Germany. Methods The entire staff of a university hospital heart center for cardiologic maximum medical care and cardiac surgery were invited to participate in a cross-sectional study (N = 575). The sampled population included health care workers as well as employees with no close patient contact. A questionnaire concerning personal and occupational risk factors as well as lifestyle and demographic factors was applied and nasal swabs were taken. In total 180 persons (31.3%) participated in the study. Results The majority of study participants had close contact to patients at work (n = 149, 82.8%). Thereof, about one-third had contact to MRSA-patients (n = 53, 35.6%), and most reported wearing protective clothing (n = 44, 83.0%). None of the administrative staff tested positive for MRSA and only one in 149 persons (0.7%, CI 0.00–0.02) with close patient contact carried MRSA (strain CC1-MRSA-IV). This person had close contact to patients with MRSA, less than 1 year of work experience, and had been treated with antibiotics within the last 12 months. Conclusion The results of our study suggest low point prevalence rates of MRSA colonization in health care workers in a non-outbreak setting.

ObjectivesWorking memory is essential for daily life skills like reading comprehension, reasoning, and problem-solving. Healthy aging of the brain goes along with working memory decline that can affect older people’s independence in everyday life. Interventions in the form of cognitive training are a promising tool for delaying age-related working memory decline, yet the underlying structural plasticity of white matter is hardly studied.MethodsWe conducted a longitudinal diffusion tensor imaging study to investigate the effects of an intensive four-week adaptive working memory training on white matter integrity quantified by global and tract-wise mean diffusivity. We compared diffusivity measures of fiber tracts that are associated with working memory of 32 young and 20 older participants that were randomly assigned to a working memory training group or an active control group.ResultsThe behavioral analysis showed an increase in working memory performance after the four-week adaptive working memory training. The neuroanatomical analysis revealed a decrease in mean diffusivity in the working memory training group after the training intervention in the right inferior longitudinal fasciculus for the older adults. There was also a decrease in mean diffusivity in the working memory training group in the right superior longitudinal fasciculus for the older and young participants after the intervention.ConclusionThis study shows that older people can benefit from working memory training by improving their working memory performance that is also reflected in terms of improved white matter integrity in the superior longitudinal fasciculus and the inferior longitudinal fasciculus, where the first is an essential component of the frontoparietal network known to be essential in working memory.

Cross-sectional studies indicate that normal aging is accompanied by decreases in brain structure. Longitudinal studies, however, are relatively rare and inconsistent regarding their outcomes. Particularly the heterogeneity of methods, sample characteristics and the high inter-individual variability in older adults prevent the deduction of general trends. Therefore, the current study aimed to compare longitudinal age-related changes in brain structure (measured through cortical thickness) in two large independent samples of healthy older adults (n = 161 each); the Longitudinal Healthy Aging Brain (LHAB) database project at the University of Zurich, Switzerland, and 1000BRAINS at the Research Center Juelich, Germany. Annual percentage changes in the two samples revealed stable to slight decreases in cortical thickness over time. After correction for major covariates, i.e., baseline age, sex, education, and image quality, sample differences were only marginally present. Results suggest that general trends across time might be generalizable over independent samples, assuming the same methodology is used, and similar sample characteristics are present.

Substantial evidence indicates that cognitive training can be efficacious for older adults, but findings regarding training-related brain plasticity have been mixed and vary depending on the imaging modality. Recent years have seen a growth in recognition of the importance of large-scale brain networks on cognition. In particular, task-induced deactivation within the default mode network (DMN) is thought to facilitate externally directed cognition, while aging-related decrements in this neural process are related to reduced cognitive performance. It is not yet clear whether task-induced deactivation within the DMN can be enhanced by cognitive training in the elderly. We previously reported durable cognitive improvements in a sample of healthy older adults (age range = 60–75) who completed 6 weeks of process-based object-location memory training (N = 36) compared to an active control training group (N = 31). The primary aim of the current study is to evaluate whether these cognitive gains are accompanied by training-related changes in task-related DMN deactivation. Given the evidence for heterogeneity of the DMN, we examine task-related activation/deactivation within two separate DMN branches, a ventral branch related to episodic memory and a dorsal branch more closely resembling the canonical DMN. Participants underwent functional magnetic resonance imaging (fMRI) while performing an untrained object-location memory task at four time points before, during, and after the training period. Task-induced (de)activation values were extracted for the ventral and dorsal DMN branches at each time point. Relative to visual fixation baseline: (i) the dorsal DMN was deactivated during the scanner task, while the ventral DMN was activated; (ii) the object-location memory training group exhibited an increase in dorsal DMN deactivation relative to the active control group over the course of training and follow-up; (iii) changes in dorsal DMN deactivation did not correlate with task improvement. These results indicate a training-related enhancement of task-induced deactivation of the dorsal DMN, although the specificity of this improvement to the cognitive task performed in the scanner is not clear.

Markers of cerebral small vessel disease (CSVD) have previously been associated with age-related cognitive decline. Using longitudinal data of cognitively healthy, older adults (N = 216, mean age at baseline = 70.9 years), we investigated baseline status and change in white matter hyperintensities (WMH) (total, periventricular, deep), normal appearing white matter (NAWM), brain parenchyma volume (BPV) and processing speed over seven years as well as the impact of different covariates by applying latent growth curve (LGC) models. Generally, we revealed a complex pattern of associations between the different CSVD markers. More specifically, we observed that changes of deep WMH (dWMH), as compared to periventricular WMH (pWMH), were more strongly related to the changes of other CSVD markers and also to baseline processing speed performance. Further, the number of lacunes rather than their volume reflected the severity of CSVD. With respect to the studied covariates, we revealed that higher education had a protective effect on subsequent total WMH, pWMH, lacunar number, NAWM volume, and processing speed performance. The indication of antihypertensive drugs was associated with lower lacunar number and volume at baseline and the indication of antihypercholesterolemic drugs came along with higher processing speed performance at baseline. In summary, our results confirm previous findings, and extend them by providing information on true within-person changes, relationships between the different CSVD markers and brain-behavior associations. The moderate to strong associations between changes of the different CSVD markers indicate a common pathological relationship and, thus, support multidimensional treatment strategies.

Background: Individuals with dissociative identity disorder (DID) have complex symptoms consistent with severe traumatic reactions. Clinicians and forensic assessors are challenged by distinguishing symptom exaggeration and feigning from genuine symptoms among these individuals. This task may be aided by administering validity measures. Objective: This study aimed to document how individuals with DID score on the Structured Inventory of Malingered Symptomatology (SIMS). The second objective was to compare coached DID simulators and healthy controls to DID patients on the SIMS’s total score and subscales. The third objective was to examine the utility rates of the SIMS in distinguishing simulated DID from clinically diagnosed DID. Method: We compared SIMS data gathered from participants from two Dutch sites, one Swiss site and one U.S. site. Sixty-three DID patients were compared to 77 coached DID simulators and 64 healthy controls on the SIMS. A multivariate analysis compared the groups on the SIMS total scores and subscales, and post-hoc Games Howell tests and univariate ANOVAs examined differences between the groups. Utility statistics assessed the accuracy of the SIMS in distinguishing clinical from simulated DID. Results: DID simulators scored significantly higher than DID individuals and healthy controls on every SIMS subscale as well as the total score. The majority (85.7%) of the individuals with DID scored above the cut-off, which is typically interpreted as indicative of possible symptom exaggeration. DID individuals scored higher than the healthy controls on every subscale except Low Intelligence, even after controlling for dissociation. The subscales and items most frequently endorsed by the DID group are consistent with symptoms associated with complex trauma exposure and dissociative reactions. The SIMS total score had a sensitivity of 96% but an unacceptably low specificity of 14%. Conclusions: The findings indicate that the instrument is not accurate in assessing potential symptom exaggeration or feigning in DID.

Pitch labeling in absolute pitch (AP), the ability to recognize the pitch class of a sound without an external reference, is effortless, fast, and presumably automatic. Previous studies have shown that pitch labeling in AP can interfere with task demands. In the current study, we used a cued auditory Go/Nogo task requiring same/different decisions to investigate both behavioral and electrophysiological correlates of increased inhibitory demands related to automatic pitch labeling. The task comprised two Nogo conditions: a Nogo condition with pitch differences larger than one semitone, and a second Nogo condition with pitch differences of only a quarter semitone. The first Nogo condition tested if auditory-related inhibition processes are generally altered in AP musicians. The second Nogo condition tested the suppressibility of the pitch labeling using a Stroop-like effect: the two tones belonged to the same pitch class but were not identical in terms of tone frequency. If pitch labeling cannot be suppressed, the conflicting information would be expected to increase the inhibitory load in AP musicians. Our data provided no evidence for an increased difficulty to inhibit a prepotent response or to suppress conflicting pitch-labeling information in AP: AP musicians showed similar commission error rates as non-AP musicians in both Nogo conditions. N2d and P3d amplitudes of AP musicians were also comparable to those of non-AP musicians. The event-related potentials (ERPs) were, however, modulated by the Nogo condition, probably indicating an effect of stimulus similarity. It is possible that, depending on the context, pitch labeling in AP musicians is not entirely automatic and can be suppressed.

Describing the trajectories of age-related change for different brain structures has been of interest in many recent studies. However, our knowledge regarding these trajectories and their associations is still limited due to small sample sizes and low numbers of repeated measures. For the present study, we used a large longitudinal dataset (four measurements over 4 years) comprising anatomical data from a sample of healthy older adults (N = 231 at baseline). This dataset enables us to gain new insights about volumetric cortical and subcortical changes and their associations in the context of healthy aging. Brain structure volumes were derived from T1-weighted MRI scans using FreeSurfer segmentation tools. Brain structure trajectories were fitted using mixed models and latent growth curve models to gain information about the mean extent and variability of decline trajectories for different brain structures as well as the associations between individual trajectories. On the group level, our analyses indicate similar linear changes for frontal and parietal brain regions, while medial temporal regions showed an accelerated decline with advancing age. Regarding subcortical regions, some structures showed strong declines (e.g., hippocampus), others showed little decline (e.g., pallidum). Our data provide little evidence for sex differences regarding the aforementioned trajectories. Between-person variability of the person-specific slopes (random slopes) was largest in subcortical and medial temporal brain structures. When looking at the associations between the random slopes from each brain structure, we found that the decline is largely homogenous across the majority of cortical brain structures. In subcortical and medial temporal brain structures, however, more heterogeneity of the decline was observed, meaning that the extent of the decline in one structure is less predictive of the decline in another structure. Taken together, our study contributes to enhancing our understanding of structural brain aging by demonstrating (1) that average volumetric change differs across the brain and (2) that there are regional differences with respect to between-person variability in the slopes. Moreover, our data suggest (3) that random slopes are highly correlated across large parts of the cerebral cortex but (4) that some brain regions (i.e., medial temporal regions) deviate from this homogeneity.

Previous studies have reported the effects of absolute pitch (AP) and musical proficiency on the functioning of specific brain regions or distinct subnetworks, but they provided an incomplete account of the effects of AP and musical proficiency on whole-brain networks. In this study, we used EEG to estimate source-space whole-brain functional connectivity in a large sample comprising AP musicians (n ​= ​46), relative pitch (RP) musicians (n ​= ​45), and Non-musicians (n ​= ​34) during resting state, naturalistic music listening, and audiobook listening. First, we assessed the global network density of the participants’ functional networks in these conditions. As revealed by cluster-based permutation testing, AP musicians showed a decreased mean degree compared to Non-musicians whereas RP musicians showed an intermediate mean degree not statistically different from Non-musicians or AP-musicians. This effect was present during naturalistic music and audiobook listening, but, crucially, not during resting state. Second, we identified the subnetworks that drove group differences in global network density using the network-based statistic approach. We found that AP musicians showed decreased functional connectivity between major hubs of the default mode network during both music and audiobook listening compared to Non-musicians. Third, we assessed group differences in global network topology while controlling for network density. We did not find evidence for group differences in the clustering coefficient and characteristic path length. Taken together, we found first evidence of diminished whole-brain functional networks in AP musicians during the perception of naturalistic auditory stimuli. These differences might reflect a complex interplay between AP ability, musical proficiency, music processing, and auditory processing per se.

Healthy aging is associated with weaker functional connectivity within resting state brain networks and stronger functional interaction between these networks. This phenomenon has been characterized as reduced functional segregation and has been investigated mainly in cross-sectional studies. Here, we used a longitudinal dataset which consisted of four occasions of resting state fMRI and psychometric cognitive ability data, collected from a sample of healthy older adults (baseline N = 232, age range: 64–87 y, age M = 70.8 y), to investigate the functional segregation of several well-defined resting state networks encompassing the whole brain. We characterized the ratio of within-network and between-network correlations via the well-established segregation index. Our findings showed a decrease over a 4-year interval in the functional segregation of the default mode, frontoparietal control and salience ventral attention networks. In contrast, we showed an increase in the segregation of the limbic network over the same interval. More importantly, the rate of change in functional segregation of the frontoparietal control network was associated with the rate of change in processing speed. These findings support the hypothesis of functional dedifferentiation in healthy aging as well as its role in cognitive function in elderly.

In the present study we investigated 90 musicians of both sexes who possess different degrees of absolute pitch (AP) using diffusion tensor imaging in association with a correlational approach and evaluated whether there are differences in perisylvian connections depending on the proficiency level of AP. We expected higher fractional anisotropy with increasing AP ability in the white matter underlying perisylvian brain areas. Results revealed a significant positive correlation between the proficiency level of AP and fractional anisotropy values in the left-sided white matter underlying the planum temporale. We interpret this result as an indicator of auditory processing differences between musicians possessing different degrees of AP, reflecting early auditory encoding and categorization processes. The present study provides further evidence for the substantial importance of the left-sided planum temporale for the ability of AP.

PURPOSE:There is a strong association between severe hyperhomocysteinemia and myopia. Thus we studied the hypothesis that even moderately increased levels of homocysteine (Hcy) might be a potentially treatable risk factor for myopia. METHODS:The Gutenberg Health Study (GHS) is a population-based, prospective, observational cohort study in Germany, including 15,010 participants aged between 35 and 74 at recruitment. The baseline examination was conducted from 2007-2012. Refraction was measured using autorefraction (HARK 599, Carl Zeiss AG, Jena, Germany). Hcy was measured by an immunoassay. We included only phakic participants without a history of corneal surgery or corneal laser treatment. We used linear regression models to evaluate the potential association between Hcy and refraction at baseline, and between Hcy and change in refraction between baseline and 5-year-follow-up examination. We used generalized estimating equation models to account for the correlation between fellow eyes. RESULTS:We included 13,749 participants, categorized as having no myopia (spherical equivalent > -0.75 D, 65.2%), low myopia (-0.75 D--2.75 D, 21.5%), moderate myopia (-3.00 D- 5.75 D, 9.8%) and high myopia (≤ -6 D, 3.5%). Median Hcy levels were similar in all groups (μmol/l). We observed no association of Hcy with refraction or 5-year change in refraction in the models adjusted for age, sex and socioeconomic status. CONCLUSION:We found no evidence for an association of Hcy levels and refractive error.

Objectives: Patients suffering from Takotsubo syndrome have a higher prevalence of anxiety and depressive disorders compared to those with acute myocardial infarction and might thus show impaired regulation and processing of emotions. Methods: In this cross-sectional study, neural activity during an emotional picture processing task was examined in 26 Takotsubo patients (on average 27 months after the Takotsubo event) and 22 healthy age- and gender-matched control subjects undergoing functional magnetic resonance imaging. Imaging data were analyzed with two complementary approaches: First, univariate analysis was used to detect brain regions showing condition-specific differences in mean neural activity between groups. Second, multivariate pattern analysis was applied to decode the experimental conditions from individual activity patterns. Results: In the univariate analysis approach, patients showed lower bilateral superior parietal activity during the processing of negative expected pictures compared to the control subjects. The multivariate pattern analysis revealed group differences in decoding negative versus neutral pictures from a widespread network consisting of frontal, parietal, occipital, and cerebellar brain regions. Additionally, differences in decoding the expectation of a negative versus positive upcoming picture were observed in the visual cortex. Conclusion: The lower involvement of brain regions observed in Takotsubo patients suggests an impairment in emotion regulation, which might be of etiological importance in this brain-heart disease. Keywords: Broken heart syndrome, Emotion regulation, Picture processing, Brain-heart connection

Abstract Takotsubo syndrome (TTS) is characterized by acute left ventricular dysfunction, with a hospital-mortality rate similar to acute coronary syndrome (ACS). However, the aetiology of TTS is still unknown. In the present study, a multivariate pattern analysis using machine learning with multimodal magnetic resonance imaging (MRI) data of the human brain of TTS patients and age- and gender-matched healthy control subjects was performed. We found consistent structural and functional alterations in TTS patients compared to the control group. In particular, anatomical and neurophysiological measures from brain regions constituting the emotional-autonomic control system contributed to a prediction accuracy of more than 82%. Thus, our findings demonstrate homogeneous neuronal alterations in TTS patients and substantiate the importance of the concept of a brain-heart interaction in TTS.

Jens Lutz,1 Kerstin Jurk,2 Helmut Schinzel3 1Nephrology Department, I. Medizinische Klinik und Poliklinik, 2Center for Thrombosis and Hemostasis, Universitätsmedizin Mainz, 3Cardiopraxis Mainz, Gerinnungsambulanz, MED Facharztzentrum, Mainz, Germany Abstract: Many patients with chronic kidney disease (CKD) receive anticoagulation or antiplatelet therapy due to atrial fibrillation, coronary artery disease, thromboembolic disease, or peripheral artery disease. The treatment usually includes vitamin K antagonists (VKAs) and/or platelet aggregation inhibitors. The direct oral anticoagulants (DOAC) inhibiting factor Xa or thrombin represent an alternative for VKAs. In patients with acute and chronic kidney disease, caution is warranted, as DOACs can accumulate as they are partly eliminated by the kidneys. Thus, they can potentially increase the bleeding risk in patients with CKD. In patients with an estimated glomerular filtration rate (eGFR) above 60 mL/min, DOACs can be used safely with greater efficacy and safety as compared to VKAs. In patients with CKD 3, DOACs are as effective as VKAs with a lower bleeding rate. The more the renal function declines, the lower is the advantage of DOACs over VKAs. Thus, use of DOACs should be avoided in patients with an eGFR below 30 mL/min, particularly, the compounds with a high renal elimination. Available data suggest that DOACs can also be used safely in older patients. In this review, use of DOACs in comparison with VKAs, heparins, and heparinoids, together with special considerations in patients with impaired renal function will be discussed. Keywords: chronic renal disease, anticoagulation, renal function, vitamin K antagonists, bleeding, atrial fibrillation, dosing

Age-related differences in white matter (WM) microstructure have been linked to lower performance in tasks of processing speed in healthy older individuals. However, only few studies have examined this link in a longitudinal setting. These investigations have been limited to the correlation of simultaneous changes in WM microstructure and processing speed. Still little is known about the nature of age-related changes in WM microstructure, i.e., regionally distinct vs. global changes. In the present study, we addressed these open questions by exploring whether previous changes in WM microstructure were related to subsequent changes in processing speed: (a) 1 year later; or (b) 2 years later. Furthermore, we investigated whether age-related changes in WM microstructure were regionally specific or global. We used data from four occasions (covering 4 years) of the Longitudinal Healthy Aging Brain (LHAB) database project (N = 232; age range at baseline = 64–86). As a measure of WM microstructure, we used mean fractional anisotropy (FA) in 10 major WM tracts averaged across hemispheres. Processing speed was measured with four cognitive tasks. Statistical analyses were conducted with bivariate latent change score (LCS) models. We found, for the first time, evidence for lagged couplings between preceding changes in FA and subsequent changes in processing speed 2 years, but not 1 year later in some of the WM tracts (anterior thalamic radiation, superior longitudinal fasciculus). Our results supported the notion that FA changes were different between regional WM tracts rather than globally shared, with some tracts showing mean declines in FA, and others remaining relatively stable across 4 years.

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.

Diabetes plays an important role in the complex relationship between chronic kidney disease (CKD) and cardiovascular disease. This retrospective observational study compared the influence of estimated glomerular filtration rate (eGFR) and proteinuria on the risk of major adverse cardiovascular event (MACE; myocardial infarction or stroke) in CKD patients with and without diabetes. Data were from a linked database of UK electronic health records. Individuals with CKD and no prior MACE were classified as type 1 diabetes (T1DM; n = 164), type 2 diabetes (T2DM; n = 9,711), and non-diabetes (non-DM; n = 75,789). Monthly updated time-dependent Cox proportional hazard models were constructed to calculate adjusted hazard ratios (aHRs) for progression to MACE from first record of abnormal eGFR or proteinuria (index date). In non-DM, aHRs (95% CIs) by baseline eGFR category (referent G2) were G1: 0.70 (0.55-0.90), G3a: 1.28 (1.20-1.35), G3b: 1.64 (1.52-1.76), G4: 2.19 (1.98-2.43), and G5: 3.12 (2.44-3.99), and by proteinuria category (referent A1) were A2: 1.13 (1.00-1.28), A2/3 (severity indeterminable): 1.58 (1.28-1.95), and A3: 1.64 (1.38-1.95). In T2DM, aHRs were G1: 0.98 (0.72-1.32), G3a: 1.18 (1.03-1.34), G3b: 1.31 (1.12-1.54), G4: 1.87 (1.53-2.29), G5: 2.87 (1.82-4.52), A2: 1.22 (1.04-1.42), A2/3: 1.45 (1.17-1.79), and A3: 1.82 (1.53-2.16). Low numbers in T1DM precluded analysis. Modelling T2DM and non-DM together, aHRs were, respectively, G1: 3.23 (2.38-4.40) and 0.70 (0.55-0.89); G2: 3.18 (2.73-3.70) and 1.00 (referent); G3a: 3.65 (3.13-4.25) and 1.28 (1.21-1.36); G3b: 4.01 (3.40-4.74) and 1.65 (1.54-1.77); G4: 5.78 (4.70-7.10) and 2.21 (2.00-2.45); G5: 9.00 (5.71-14.18) and 3.14 (2.46-4.00). In conclusion, reduced eGFR and proteinuria were independently associated with increased risk of MACE regardless of diabetes status. However, the risk of MACE in the same eGFR state was 4.6-2.4 times higher in T2DM than in non-DM.

Objectives: We investigated whether patients with complex interpersonal trauma engage neural networks that are commonly activated during cognitive reappraisal and responding naturally to affect-laden images. In this naturalistic study, we examined whether trauma treatment not only reduces symptoms but also changes neural networks involved in emotional control. Methods: Before and after eight weeks of phase-oriented inpatient trauma treatment, patients (n = 28) with complex posttraumatic stress disorder (cPTSD) and complex dissociative disorders (CDD) performed a cognitive reappraisal task while electroencephalography (EEG) was registered. Patients were measured as a prototypical dissociative part that aims to fulfill daily life goals while avoiding traumatic memories and associated dissociative parts. Matched healthy controls (n = 38) were measured twice as well. We examined task-related functional connectivity and assessed self-reports of clinical symptoms and emotion regulation skills. Results: Prior to treatment and compared to controls, patients showed hypoconnectivity within neural networks involved in emotional downregulation while reappraising affect-eliciting pictures as well as viewing neutral and affect-eliciting pictures. Following treatment, connectivity became normalized in these networks comprising regions associated with cognitive control and memory. Additionally, patients showed a treatment-related reduction of negative but not of positive dissociative symptoms. Conclusions: This is the first study demonstrating that trauma-focused treatment was associated with favorable changes in neural networks involved in emotional control. Emotional overregulation manifesting as negative dissociative symptoms was reduced but not emotional underregulation, manifesting as positive dissociative symptoms. Keywords: Complex trauma, Dissociation, Electroencephalography, Functional brain network, Network-based statistic, Trauma treatment, Emotion regulation

ST239-MRSA-III is probably the oldest truly pandemic MRSA strain, circulating in many countries since the 1970s. It is still frequently isolated in some parts of the world although it has been replaced by other MRSA strains in, e.g., most of Europe. Previous genotyping work (Harris et al., 2010; Castillo-Ramírez et al., 2012) suggested a split in geographically defined clades. In the present study, a collection of 184 ST239-MRSA-III isolates, mainly from countries not covered by the previous studies were characterized using two DNA microarrays (i) targeting an extensive range of typing markers, virulence and resistance genes and (ii) a SCCmec subtyping array. Thirty additional isolates underwent whole-genome sequencing (WGS) and, together with published WGS data for 215 ST239-MRSA-III isolates, were analyzed using in-silico analysis for comparison with the microarray data and with special regard to variation within SCCmec elements. This permitted the assignment of isolates and sequences to 39 different SCCmec III subtypes, and to three major and several minor clades. One clade, characterized by the integration of a transposon into nsaB and by the loss of fnbB and splE was detected among isolates from Turkey, Romania and other Eastern European countries, Russia, Pakistan, and (mainly Northern) China. Another clade, harboring sasX/sesI is widespread in South-East Asia including China/Hong Kong, and surprisingly also in Trinidad & Tobago. A third, related, but sasX/sesI-negative clade occurs not only in Latin America but also in Russia and in the Middle East from where it apparently originated and from where it also was transferred to Ireland. Minor clades exist or existed in Western Europe and Greece, in Portugal, in Australia and New Zealand as well as in the Middle East. Isolates from countries where this strain is not epidemic (such as Germany) frequently are associated with foreign travel and/or hospitalization abroad. The wide dissemination of this strain and the fact that it was able to cause a hospital-borne pandemic that lasted nearly 50 years emphasizes the need for stringent infection prevention and control and admission screening.

The influence of background music on cognitive functions is still a matter of debate. In this study, we investigated the influence of background music on executive functions (particularly on inhibitory functions). Participants completed a standardized cued Go/NoGo task during three different conditions while an EEG was recorded (1: with no background music, 2: with relaxing, or 3: with exciting background music). In addition, we collected reaction times, omissions, and commissions in response to the Go and NoGo stimuli. From the EEG data, event-related potentials (ERPs) were calculated for the Go and NoGo trials. From these ERPs, the N2 and P3 components were specifically analyzed since previous studies have shown that these components (and particularly the Go-NoGo difference waves) are strongly associated with inhibitory functions. The N2 and P3 components of the difference waves (N2d and P3d) were used for statistical analyses. The statistical analyses revealed no differences between the three conditions in terms of amplitudes and latencies of the N2d and P3d components. In addition, reaction times, omissions, and commissions were comparable across all conditions. Our results suggest that in the context of this paradigm, music as background acoustic stimulation has no detrimental effects on the performance of a Go/NoGo task and neural underpinnings.

In this mini-review, I summarize and interpret the current status of sex/gender differences in terms of brain anatomy, brain function, behavior, and cognition. Based on this review and the reported findings, I conclude that most of these sex/gender differences are not large enough to support the assumption of sexual dimorphism in terms of brain anatomy, brain function, cognition, and behavior. Instead, I suggest that many brain and cognitive features are modulated by environment, culture, and practice (and several other influences). These influences interact with the menstrual cycle, the general hormone level, and current gender stereotypes in a way that has not yet been fully understood.

Language in its highest complexity is a unique human faculty with simultaneous translation being among the most demanding language task involving both linguistic and executive functions. In this context, bilingually grown up individuals as well as simultaneous interpreters (SIs) represent appropriate groups for studying expertise-related neural adaptations in the human brain. The present study was performed to examine if a domain-specific neural network activation pattern, constituted by brain regions involved in speech processing as well as cognitive control mechanisms can be detected during a task-free resting state condition. To investigate this, electroencephalographic (EEG) data were recorded from 16 SIs and 16 age and gender-matched multilingual control subjects. Graph-theoretical network analyses revealed interhemispheric hyperconnectivity between the ventral part of the prefrontal cortex (pars opercularis and pars triangularis) and the dorsolateral prefrontal cortex (DLPFC) in language experts compared to multilingual controls in the alpha frequency range. This finding suggests that the high cognitive demands placed on simultaneous interpreting lead to an increased neural communication between prefrontal brain regions essentially engaged in supporting executive control-a neural fingerprint that is even detectable during rest.

Aging is associated with microstructural white matter (WM) changes. WM microstructural characteristics, measured with diffusion tensor imaging (DTI), are different in normal appearing white matter (NAWM) and WM hyperintensities (WMH). It is largely unknown how the microstructural properties of WMH are associated with cognition and if there are regional effects for specific cognitive domains. We therefore examined within 200 healthy older participants (a) differences in microstructural characteristics of NAWM and WMH per cerebral lobe; and (b) the association of macrostructural (WMH volume) and microstructural characteristics (within NAWM and WMH separately) of each lobe with measures of executive function and processing speed. Multi-modal imaging (i.e., T1, DTI, and FLAIR) was used to assess WM properties. The Stroop and the Trail Making Test were used to measure inhibition, task-switching (both components of executive function), and processing speed. We observed that age was associated with deterioration of white matter microstructure of the NAWM, most notably in the frontal lobe. Older participants had larger WMH volumes and lowest fractional anisotropy values within WMH were found in the frontal lobe. Task-switching was associated with cerebral NAWM volume and NAWM volume of all lobes. Processing speed was associated with total NAWM volume, and microstructural properties of parietal NAWM, the parietal WMH, and the temporal NAWM. Task-switching was related to microstructural properties of WMH of the frontal lobe and WMH volume of the parietal lobe. Our results confirm that executive functioning and processing speed are uniquely associated with macro- and microstructural properties of NAWM and WMH. We further demonstrate for the first time that these relationships differ by lobar region. This warrants the consideration of these distinct WM indices when investigating cognitive function.

In this paper, we examined brain activation in subjects during two music listening conditions: listening while simultaneously rating the musical piece being played [Listening and Rating (LR)] and listening to the musical pieces unconstrained [Listening (L)]. Using these two conditions, we tested whether the sequence in which the two conditions were fulfilled influenced the brain activation observable during the L condition (LR → L or L → LR). We recorded high-density EEG during the playing of four well-known positively experienced soundtracks in two subject groups. One group started with the L condition and continued with the LR condition (L → LR); the second group performed this experiment in reversed order (LR → L). We computed from the recorded EEG the power for different frequency bands (theta, lower alpha, upper alpha, lower beta, and upper beta). Statistical analysis revealed that the power in all examined frequency bands increased during the L condition but only when the subjects had not had previous experience with the LR condition (i.e., L → LR). For the subjects who began with the LR condition, there were no power increases during the L condition. Thus, the previous experience with the LR condition prevented subjects from developing the particular mental state associated with the typical power increase in all frequency bands. The subjects without previous experience of the LR condition listened to the musical pieces in an unconstrained and undisturbed manner and showed a general power increase in all frequency bands. We interpret the fact that unconstrained music listening was associated with increased power in all examined frequency bands as a neural indicator of a mental state that can best be described as a mind-wandering state during which the subjects are “drawn into” the music.

Brain connectivity after mild traumatic brain injury (mTBI) has not been investigated longitudinally with respect to both functional and structural networks together within the same patients, crucial to capture the multifaceted neuropathology of the injury and to comprehensively monitor the course of recovery and compensatory reorganizations at macro-level. We performed a prospective study with 49 mTBI patients at an average of 5 days and 1 year post-injury and 49 healthy controls. Neuropsychological assessments as well as resting-state functional and diffusion-weighted magnetic resonance imaging were obtained. Functional and structural connectome analyses were performed using network-based statistics. They included a cross-sectional group comparison and a longitudinal analysis with the factors group and time. The latter tracked the subnetworks altered at the early phase and, in addition, included a whole-brain group × time interaction analysis. Finally, we explored associations between the evolution of connectivity and changes in cognitive performance. The early phase of mTBI was characterized by a functional hypoconnectivity in a subnetwork with a large overlap of regions involved within the classical default mode network. In addition, structural hyperconnectivity in a subnetwork including central hub areas such as the cingulate cortex was found. The impaired functional and structural subnetworks were strongly correlated and revealed a large anatomical overlap. One year after trauma and compared to healthy controls we observed a partial normalization of both subnetworks along with a considerable compensation of functional and structural connectivity subsequent to the acute phase. Connectivity changes over time were correlated with improvements in working memory, divided attention, and verbal recall. Neuroplasticity-induced recovery or compensatory processes following mTBI differ between brain regions with respect to their time course and are not fully completed 1 year after trauma.

Ulrike Kaiser,1 Bernhard Arnold,2 Michael Pfingsten,3 Bernd Nagel,4 Johannes Lutz,5 Rainer Sabatowski1,61Comprehensive Pain Center, University Hospital “Carl Gustav Carus”, Dresden, 2Department of Pain Management, Klinikum Dachau, Dachau, 3Pain Clinic, University Medicine, University of Göttingen, 4Day Care Unit, DRK Pain Center, Mainz, 5Interdisciplinary Pain Center, Zentralklinik Bad Berka, Bad Berka, 6Department of Anesthesiology and Intensive Care, University Hospital “Carl Gustav Carus”, Dresden, Germany

Background: Cultural neuroscience is an emerging research field concerned with studying the influences of different cultures on brain anatomy and function. In this study we examined whether different cultural or genetic influences might influence the resting state electroencephalogram (EEG) in young children (mean age 10 years) from Switzerland and Saudi Arabia. Methods: Resting state EEG recordings were obtained from relatively large groups of healthy children (95 healthy Swiss children and 102 Saudi Arabian children). These EEG data were analyzed using group independent component analyses and conventional analyses of spectral data, together with estimations of the underlying intracortical sources, using LORETA software.Results: We identified many similarities, but also some substantial differences with respect to the resting state EEG data. For Swiss children, we found stronger delta band power values in mesial frontal areas and stronger power values in 3 out of 4 frequency bands in occipital areas. For Saudi Arabian children, we uncovered stronger alpha band power over the sensorimotor cortex. The additionally measured theta/beta ratio was similar for Swiss and Saudi Arabian children. Conclusions: The different EEG resting state features identified, are discussed in the context of different cultural experiences and possible genetic influences. In addition, we emphasize the importance of using appropriate EEG databases when comparing resting state EEG features between groups. Keywords: intercultural neuroscience, EEG, resting state EEG, children, LORETA, group independent component analysis.

Humans and higher primates are unique in that they lack uricase, the enzyme capable of oxidizing uric acid. As a consequence of this enzyme deficiency, humans have high serum uric acid levels. In some people, uric acid levels rise above the solubility limit resulting in crystallization in joints, acute inflammation in response to those crystals causes severe pain; a condition known as gout. Treatment for severe gout includes injection of non-human uricase to reduce serum uric acid levels. Krystexxa® is a hyper-PEGylated pig-baboon chimeric uricase indicated for chronic refractory gout that induces an immunogenic response in 91% of treated patients, including infusion reactions (26%) and anaphylaxis (6.5%). These properties limit its use and effectiveness. An innovative approach has been used to develop a therapeutic uricase with improved properties such as: soluble expression, neutral pH solubility, high E. coli expression level, thermal stability, and excellent activity. More than 200 diverse uricase sequences were aligned to guide protein engineering and reduce putative sequence liabilities. A single uricase lead candidate was identified, which showed low potential for immunogenicity in >200 human donor samples selected to represent diverse HLA haplotypes. Cysteines were engineered into the lead sequence for site specific PEGylation and studies demonstrated >95% PEGylation efficiency. PEGylated uricase retains enzymatic activity in vitro at neutral pH, in human serum and in vivo (rats and canines) and has an extended half-life. In canines, an 85% reduction in serum uric acid levels was observed with a single subcutaneous injection. This PEGylated, non-immunogenic uricase has the potential to provide meaningful benefits to patients with gout.