Search

Eph-receptors represent the largest family of receptor tyrosine kinases. Eph-receptors and their cognate ephrin-ligands are cell-surface proteins, which are able to generate bidirectional signaling. Eph/ephrin interactions are essential in a variety of processes like tumor biology and inflammation. However, the impact of Eph/ephrin-interactions in the pathophysiology of atherosclerosis is still not well understood. The aim of the present study was to investigate the involvement of the Eph/ephrin-system in the TNF-α mediated monocyte adhesion.Human umbilical vein endothelial cells (HUVEC) were treated with TNF-α and the expression of different ephrin-ligands and Eph-receptors was analyzed on mRNA and protein level. EphrinA1 was found to be highly induced by TNF-α stimulation. This induction is mediated by NFkB, as overexpression of a constitutive active IkB mutant completely abolished the ephrinA1 induction. Previous results of our group showed an involvement of ephrinA1 in the process of monocyte adhesion to endothelial cells. Therefore, the impact of TNF-α mediated ephrinA1 induction in monocyte adhesion was studied. The siRNA-mediated silencing of ephrinA1 in endothelial cells, leads to a reduction of monocyte adhesion to TNF-α stimulated endothelial cells. Using a Single-Cell-Force-Spectroscopy approach we could confirm these results. The detachment forces of monocytes from endothelial cells increase after TNF-α stimulation and more importantly were decreased in ephrinA1-silenced endothelial cells. The decrease in monocyte adhesion was accompanied by reduced cell-surface expression of VCAM-1 and ICAM-1 in TNF-α-stimulated and ephrinA1-silenced cells compared to control-transfected cells. Interestingly, the overall expression of VCAM-1 and ICAM-1 on mRNA and protein level was not influenced by ephrinA1 silencing. In contrast, the overexpression of ephrinA1 in endothelial cells shows contrary effects. Ephrin-A1 overexpression enhances the TNF-α mediated monocyte adhesion to endothelial cells as well as the detachment forces.In conclusion, these data demonstrate that endothelial ephrinA1 is induced by TNF-α in a NFkB dependent manner. This induction of ephrinA1 by TNF-α in endothelial cells represents a crucial part of the proadhesive effect of TNF-α on monocytes. Mechanistically it can be shown, that ephrinA1 regulates the trafficking of adhesion molecules and therefore the presentation on the cell surface of endothelial cells. These results might open perspectives by defining a new role of ephrinA1 in TNF-α induced inflammatory processes like monocyte adhesion in atherosclerotic plaques. [ABSTRACT FROM PUBLISHER]

The Eph-family, consisting of Eph-receptors and ephrin-ligands represents the largest class of receptor tyrosine-kinases. The role of Eph/ephrins in elementary physiological processes as re-endothelialisation is still not well understood. The aim of the present study was to investigate the regulation of the ligand ephrin-A1 and its potential impact on proliferation and migration of human umbilical venous (HUVEC) and arterial endothelial cells (HUAEC).Initially, it could be shown, that ephrin-A1 expression was positively correlated with the density of the endothelial cells. Thus, a significant induction of ephrin-A1 in endothelial cells was observed after contact inhibition. The impact of ephrin-A1 on endothelial proliferation and migration was studied using siRNA and adenoviral overexpression. The siRNA-mediated silencing of ephrin-A1 in HUVEC increased the proliferation. In contrast, adenoviral overexpression of ephrin-A1 decreased the proliferation, suggesting an involvement of ephrin-A1 in endothelial proliferation. To study the role of ephrin-A1 in processes associated with an endothelial defect, a wound healing assay was performed. Ephrin-A1-silenced HUVEC showed a faster gap area closure in comparison to cells transfected with a scrambled control siRNA. Interestingly, ephrin-A1-overexpressing endothelial cells showed a faster gap area closure compared to lacZ-control as well. Using live cell imaging it could be visualized that the silencing of ephrin-A1 influences the direction of the migration of HUVEC resulting in disorientation and a missing polarization of the cells. Overexpression of ephrin-A1 leads to a straight forward and faster migration compared to the controls. By using baculoviral expression of actin-GFP and talin-RFP accordingly both the silencing and the overexpression of ephrin-A1 resulted in an increased number of endothelial focal adhesions which also influenced the actin-cytoskeleton in endothelial cells. A migration assay was established to investigate endothelial response to contact with an ephrin-A1-coated surface. A temporary stop of migration was observed after surface coating with ephrin-A1-Fc. Taken together, these results show that ephrin-A1-expression depends on cell-density and is a critical determinant of endothelial proliferation. Furthermore, ephrinA1 is involved in the regulation of migration of cells, by modulating the speed of migration and more importantly the direction of migration. These results show, that ephrinA1 is highly involved in the process of wound healing which is amongst others of great importance for re-endothelialisation. [ABSTRACT FROM AUTHOR]

Childhood maltreatment (CM) is known to influence brain development. To obtain a better understanding of related brain alterations, recent research has focused on the influence of the type and timing of CM. We aimed to investigate the association between type and timing of CM and local brain volume. Anatomical magnetic resonance images were collected from 93 participants (79 female/14 male) with a history of CM. CM history was assessed with the German Interview Version of the "Maltreatment and Abuse Chronology of Exposure" scale, "KERF-40 + ". Random forest regressions were performed to assess the impact of CM characteristics on the volume of amygdala, hippocampus and anterior cingulate cortex (ACC). The volume of the left ACC was predicted by neglect at age 3 and 4 and abuse at age 16 in a model including both type and timing of CM. For the right ACC, overall CM severity and duration had the greatest impact on volumetric alterations. Our data point to an influence of CM timing on left ACC volume, which was most pronounced in early childhood and in adolescence. We were not able to replicate previously reported effects of maltreatment type and timing on amygdala and hippocampal volume., (© 2024. The Author(s).)

The routine in-depth characterization of patients with methods of clinical and scale-based examination, neuropsychology, based on biomaterials, and sensor-based information opens up transformative possibilities on the way to personalized diagnostics, treatment and prevention in psychiatry, psychotherapy, and psychosomatics. Effective integration of the additional temporal and logistical effort into everyday care as well as the acceptance by patients are critical to the success of such an approach but there is little evidence on this to date. We report here on the establishment of the Diagnosis and Admission Center (DAZ) at the Central Institute of Mental Health (ZI) in Mannheim. The DAZ is an outpatient unit upstream of other care structures for clinical and scientific phenotyping across diagnoses as a starting point for data-driven, individualized pathways to further treatment, diagnostics or research. We describe the functions, goals, and implementation of the newly created clinical scientific translational structure, provide an overview of the patient populations it has reached, and provide data on its acceptance. In this context, the close integration with downstream clinical processes enables a better coordinated and demand-oriented allocation. In addition, DAZ enables a faster start of disorder-specific diagnostics and treatment. Since its launch in April 2021 up to the end of 2022, 1021 patients underwent psychiatric evaluation at DAZ during a pilot phase. The patient sample corresponded to a representative sample from standard care and the newly established processes were regarded as helpful by patients. In summary, the DAZ uniquely combines the interests and needs of patient with the collection of scientifically relevant data., (© 2024. The Author(s).)

Background: Adverse childhood experiences (ACE), which can be separated into abuse and neglect, contribute to the development of post-traumatic stress symptoms (PTSS). However, which brain structures are mainly affected by ACE as well as the mediating role these brain structures play in ACE and PTSS relationship are still being investigated. The current study tested the effect of ACE on brain structure and investigated the latter's mediating role in ACE-PTSS relationship., Methods: A total of 78 adults with self-reported ACE were included in this study. Participants completed the childhood trauma questionnaire (CTQ) and a Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) to ascertain ACE history and PTSS, respectively. T1w images and diffusion MRI scans were then acquired to assess cortical morphometry and white matter (WM) integrity in fibre tracts connecting key areas where ACE-related cortical volume alterations were observed., Results: The combined effect of ACE was negatively associated with total grey matter volume and local cortical area in the right superior parietal region (rSP). Childhood abuse was negatively related to right superior parietal volume after controlling for neglect and overall psychological burden. The right superior parietal volume significantly mediated the relationship between childhood abuse and avoidance-related PTSS. Post-hoc analyses showed that the indirect relation was subsequently moderated by dissociative symptoms. Lastly, a complementary examination of the WM tracts connected to abuse-associated cortical GM regions shows that abuse was negatively related to the normalised fibre density of WM tracts connected to the right superior parietal region., Conclusion: We provide multimodal structural evidence that ACE in the first years of life is related to alterations in the right superior brain region, which plays a crucial role in spatial processing and attentional functioning. Additionally, we highlight that the cortical volume alteration in this region may play a role in explaining the relationship between childhood abuse and avoidance symptoms., Competing Interests: None, (© 2023 The Authors.)

The learning of new facial identities and the recognition of familiar faces are crucial processes for social interactions. Recently, a combined computational modeling and functional magnetic resonance imaging (fMRI) study used predictive coding as a biologically plausible framework to model face identity learning and to relate specific model parameters with brain activity (Apps and Tsakiris, Nat Commun 4, 2698, 2013). On the one hand, it was shown that behavioral responses on a two-option face recognition task could be predicted by the level of contextual and facial familiarity in a computational model derived from predictive-coding principles. On the other hand, brain activity in specific brain regions was associated with these parameters. More specifically, brain activity in the superior temporal sulcus (STS) varied with contextual familiarity, whereas activity in the fusiform face area (FFA) covaried with the prediction error parameter that updated facial familiarity. Literature combining fMRI assessments and computational modeling in humans still needs to be expanded. Furthermore, prior results are largely not replicated. The present study was, therefore, specifically set up to replicate these previous findings. Our results support the original findings in two critical aspects. First, on a group level, the behavioral responses were modeled best by the same computational model reported by the original authors. Second, we showed that estimates of these model parameters covary with brain activity in specific, face-sensitive brain regions. Our results thus provide further evidence that the functional properties of the face perception network conform to central principles of predictive coding. However, our study yielded diverging findings on specific computational model parameters reflected in brain activity. On the one hand, we did not find any evidence of a computational involvement of the STS. On the other hand, our results showed that activity in the right FFA was associated with multiple computational model parameters. Our data do not provide evidence for functional segregation between particular face-sensitive brain regions, as previously proposed., (Copyright © 2023. Published by Elsevier Ltd.)

Left ventricular (LV) myocardial mass is important in the evaluation of cardiac remodeling and requires accurate assessment when performed on linear measurements in two-dimensional echocardiography (Echo). We aimed to compare the accuracy of the Devereaux formula (DEV) and the Teichholz formula (TEICH) in calculating LV myocardial mass in Echo using cardiac magnetic resonance (CMR) as the reference method. Based on preceding mathematical calculations, we identified primarily LV size rather than wall thickness as the main source of bias between DEV and TEICH in a retrospective derivation cohort (n = 1276). Although LV mass from DEV and TEICH were correlated with CMR, TEICH did not show a proportional bias as did DEV (- 2 g/m 2 vs. + 22 g/m 2 ). This could be validated in an independent prospective cohort (n = 226) with symptomatic non-ischemic heart failure. DEV systematically overestimated LV mass in all tiers of LV remodeling as compared to TEICH. In conclusion, the TEICH method accounts for the changes in LV geometry with increasing LV mass and thus better reflects the different pattern of LV remodeling than the DEV method. This has important clinical implications, as TEICH may be more appropriate for use in clinical practice, rather than DEV, currently recommended., (© 2023. Springer Nature Limited.)

The key players of the hypoxic response are the hypoxia-inducible factors (Hif), whose α-subunits are tightly regulated by Prolyl-4-hydroxylases (PHD), predominantly by PHD2. Monocytes/Macrophages are involved in atherosclerosis but also restenosis and were found at hypoxic and sites of the lesion. Little is known about the role of the myeloid PHD2 in atherosclerosis and neointima formation. The study aimed to investigate the consequences of a myeloid deficiency of PHD2 in the process of neointima formation using an arterial denudation model. LysM-cre mice were crossed with PHD2 fl/fl , PHD2 fl/fl /Hif1α fl/fl and PHD2 fl/fl /Hif2α fl/fl to get myeloid specific knockout of PHD2 and the Hif-α subunits. Denudation of the femoral artery was performed and animals were fed a western type diet afterwards with analysis of neointima formation 5 and 35 days after denudation. Increased neointima formation in myeloid PHD2 knockouts was observed, which was blunted by double-knockout of PHD2 and Hif1α whereas double knockout of PHD2 and Hif-2α showed comparable lesions to the PHD2 knockouts. Macrophage infiltration was comparable to the neointima formation, suggesting a more inflammatory reaction, and was accompanied by increased intimal VEGF-A expression. Collagen-content inversely correlated to the extent of neointima formation suggesting a destabilization of the plaque. This effect might be triggered by macrophage polarization. Therefore, in vitro results showed a distinct expression pattern in differentially polarized macrophages with high expression of Hif-1α, VEGF and MMP-1 in proinflammatory M1 macrophages. In conclusion, the results show that myeloid Hif-1α is involved in neointima hyperplasia. Our in vivo and in vitro data reveal a central role for this transcription factor in driving plaque-vascularization accompanied by matrix-degradation leading to plaque destabilization., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Acute right heart failure is a life-threatening condition that can arise postoperatively. The options for symptomatic treatment have been markedly expanded in recent years through the introduction of percutaneously implantable mechanical cardiac support systems., Methods: This review is based on publications retrieved by a selective literature search in PubMed as well as on guidelines from Germany and abroad., Results: The diagnostic evaluation of right heart failure is chiefly based on echocardiography and pulmonary arterial catheteri - zation and is intended to lead to immediate treatment. Alongside treatment of the cause of the condition, supportive management is crucial to patient survival. A variety of ventilation strategies depending on the situation, catecholamine therapies, inhaled selective pulmonary vasodilators, and cardiac support systems are available for this purpose. The in-hospital mortality of postoperative right heart failure is 5-17 %. The results of the use of cardiac support systems reported in case series are dis - appointing, but nonetheless good compared to what these critically ill patients would face without such treatment. In one observational study, the 30-day survival rate was 73.3%., Conclusion: Survival is aided by the rapid recognition of right heart failure, targeted multidisciplinary treatment, and contact with an extracorporeal life support (ECLS) center for additional supportive treatment measures. Further studies on the use of pharmacological and mechanical cardiac support systems must be carried out to provide stronger evidence on which treatment recommendations can be based.

Introduction: Arterial spin labeling (ASL) is a functional neuroimaging technique that has been frequently used to investigate acute pain states. A major advantage of ASL as opposed to blood-oxygen-level-dependent functional neuroimaging is its applicability for low-frequency designs. As such, ASL represents an interesting option for studies in which repeating an experimental event would reduce its ecological validity. Whereas most ASL pain studies so far have used thermal stimuli, to our knowledge, no ASL study so far has investigated pain responses to sharp mechanical pain., Methods: As a proof of concept, we investigated whether ASL has the sensitivity to detect brain activation within core areas of the nociceptive network in healthy controls following a single stimulation block based on 96 s of mechanical painful stimulation using a blunt blade., Results: We found significant increases in perfusion across many regions of the nociceptive network such as primary and secondary somatosensory cortices, premotor cortex, posterior insula, inferior parietal cortex, parietal operculum, temporal gyrus, temporo-occipital lobe, putamen, and the cerebellum. Contrary to our hypothesis, we did not find any significant increase within ACC, thalamus, or PFC. Moreover, we were able to detect a significant positive correlation between pain intensity ratings and pain-induced perfusion increase in the posterior insula., Conclusion: We demonstrate that ASL is suited to investigate acute pain in a single event paradigm, although to detect activation within some regions of the nociceptive network, the sensitivity of our paradigm seemed to be limited. Regarding the posterior insula, our paradigm was sensitive enough to detect a correlation between pain intensity ratings and pain-induced perfusion increase. Previous experimental pain studies have proposed that intensity coding in this region may be restricted to thermal stimulation. Our result demonstrates that the posterior insula encodes intensity information for mechanical stimuli as well., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Purpose: Heating of gradient coils and passive shim components is a common cause of instability in the B 0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites., Method: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC)., Results: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI., Discussion: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed., Competing Interests: Declaration of Competing Interest Jack J. Miller would like to acknowledge the support of a Novo Nordisk Research Fellowship run in conjunction with the University of Oxford. Francisco Reyes-Madrigal has served as a speaker for Janssen (Johnson & Johnson) and AstraZeneca. Marc Thioux and Pim van Dijk were supported by The Netherlands Organization for Health Research and Development (ZonMW) and the Dorhout Mees Foundation. All other authors have no conflict of interest to declare., (Copyright © 2021. Published by Elsevier Inc.)

Opioid-dependent patients frequently show deficits in multiple cognitive domains that might impact on their everyday life performance and interfere with therapeutic efforts. To date, the neurobiological underpinnings of those deficits remain to be determined. We investigated working memory performance and gray matter volume (GMV) differences in 17 patients on opioid maintenance treatment (OMT) and 17 healthy individuals using magnetic resonance imaging and voxel-based morphometry. In addition, we explored associations between substance intake, gray matter volume, and working memory task performance. Patients on OMT committed more errors during the working memory task than healthy individuals and showed smaller insula and putamen GMV. The duration of heroin use prior to OMT was associated with working memory performance and insula GMV in patients. Neither the substitution agent (methadone and buprenorphine) nor concurrent abuse of illegal substances during the 3 months prior to the experiment was significantly associated with GMV. Results indicate that impaired working memory performance and structural deficits in the insula of opioid-dependent patients are related to the duration of heroin use. This suggests that early inclusion into OMT or abstinence-oriented therapies that shorten the period of heroin abuse may limit the impairments to GMV and cognitive performance of opioid-dependent individuals.

In this report, we present cross-sectional and longitudinal findings from single-voxel MEGA-PRESS MRS of GABA as well as Glu, and Glu + glutamine (Glx) concentrations in the ACC of treatment-seeking alcohol-dependent patients (ADPs) during detoxification (first 2 weeks of abstinence). The focus of this study was to examine whether the amount of benzodiazepine administered to treat withdrawal symptoms was associated with longitudinal changes in Glu, Glx, and GABA. The tNAA levels served as an internal quality reference; in agreement with the vast majority of previous reports, these levels were initially decreased and normalized during the course of abstinence in ADPs. Our results on Glu and Glx support hyperglutamatergic functioning during alcohol withdrawal, by showing higher ACC Glu and Glx levels on the first day of detoxification in ADPs. Withdrawal severity is reflected in cumulative benzodiazepine requirements throughout the withdrawal period. The importance of withdrawal severity for the study of GABA and Glu changes in early abstinence is emphasized by the benzodiazepine-dependent Glu, Glx, and GABA changes observed during the course of abstinence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Weber-Fahr, Frischknecht, Hermann, Kiefer, Ende and Sack.)

Objective: Brain atlases are important research tools enabling researchers to focus their investigations on specific anatomically defined brain regions and are used in many MRI applications, e.g. in fMRI, morphometry, whole brain spectroscopy, et cetera. Despite their extensive use and numerous versions they usually consist of predefined rigid brain regions with a given level of detail often degrading them to a non-ideal tool in special research topics., Result: To overcome this intrinsic weakness we present a graphical user interface application which allows researchers to easily create mouse brain atlases with an adjustable user-defined level of detail and coverage to match specific research questions.

Background: Severe heart rhythm disturbances (SHRDs) occur regularly in cardiogenic shock (CS). Percutaneous left ventricular assist devices (pLVADs) can actively unload the left ventricle (LV), decreasing left ventricular end-diastolic pressure and wall tension, which are suspected parameters for the induction and maintenance of arrhythmias. The aim of this study was to describe effects of LV unloading on SHRD., Method: In the Dresden Impella Registry, 97 patients received an Impella CP in refractory CS. Of them, 19 had SHRDs, which were not stopped by common therapeutic strategies such as electrical defibrillation or antiarrhythmic drugs. They were only stopped after implantation of a micro-axial heart pump. This phenomenon was referred to as heart rhythm stabilisation (HRS). Clinical outcome and laboratory parameters were assessed and risk factors for the occurrence of HRS were identified., Results: All 19 patients with refractory SHRD terminated immediately into a stable heart rhythm after insertion of the micro-axial heart pump. In 37% no additional defibrillation was needed. Of the patients with HRS, CS was mostly caused by myocardial infarction (68%). Resuscitation before pLVAD was performed in 89% for more than 30 minutes. Patients with HRS were resuscitated more frequently and for a longer duration than patients without HRS. After HRS, the serum lactate and norepinephrine dosage decreased in the first 12 hours, whereas left ventricular ejection fraction increased by 95%., Conclusions: Left ventricular unloading in patients with CS seems to be an option for treating patients with sustained life-threatening tachycardia, who are refractory to common treatment., (Copyright © 2020 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Alcohol Use Disorder has been associated with impairments of functional connectivity between neural networks underlying reward processing and cognitive control. Evidence for aberrant functional connectivity between the striatum, insula, and frontal cortex in alcohol users exists at rest, but not during cue-exposure. In this study, we investigated functional connectivity changes during a cue-reactivity task across different subgroups of alcohol consumers. Ninety-six participants (ranging from light social to heavy social drinkers and nonabstinent dependent to abstinent dependent drinkers) were examined. A functional magnetic resonance imaging cue-reactivity paradigm was administered, during which alcohol-related and neutral stimuli were presented. Applying psychophysiological interaction analyses, we found: (a) Abstinent alcohol-dependent patients compared with non-abstinent dependent drinkers showed a greater increase of functional connectivity of the ventral striatum and anterior insula with the anterior cingulate cortex and dorsolateral prefrontal cortex during the presentation of alcohol cues compared with neutral cues. (b) Subjective craving correlated positively with functional connectivity change between the posterior insula and the medial orbitofrontal cortex and negatively with functional connectivity change between the ventral striatum and the anterior cingulate cortex, dorsolateral prefrontal cortex, and lateral orbitofrontal cortex. (c) Compulsivity of alcohol use correlated positively with functional connectivity change between the dorsolateral prefrontal cortex and the ventral striatum, anterior insula, and posterior insula. Results suggest increased cognitive control over cue-processing in abstinent alcohol-dependent patients, compensating high levels of cue-provoked craving and compulsive use. Clinical trial registration details: ClinicalTrials.gov ID: NCT00926900., (© 2020 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted P boot ). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N -acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol ( P boot > .90), N -acetylaspartate and N -acetylaspartylglutamate ( P boot = .13), or glutamate and glutamine ( P boot = .11). Among the smaller resonances, no vendor effects were found for ascorbate ( P boot = .08), aspartate ( P boot > .90), glutathione ( P boot > .90), or lactate ( P boot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article.

Deleterious effects of adverse childhood experiences (ACE) on human brain volume are widely reported. First evidence points to differential effects of ACE on brain volume in terms of timing of ACE. Upcoming studies additionally point towards the impact of different types (i.e., neglect and abuse) of ACE in terms of timing. The current study aimed to investigate the correlation between retrospectively reported severity of type (i.e., the extent to which subjects were exposed to abuse and/or neglect, respectively) and timing of ACE on female brain volume in a sample of prolonged traumatized subjects. A female sample with ACE (N = 68) underwent structural magnetic resonance imaging and a structured interview exploring the severity of ACE from age 3 up to 17 using the "Maltreatment and Abuse Chronology of Exposure" (MACE). Random forest regression with conditional interference trees was applied to assess the impact of ACE severity as well as the severity of ACE type, (i.e. to what extent individuals were exposed to neglect and/or abuse) at certain ages on pre-defined regions of interest such as the amygdala, hippocampus, and anterior cingulate (ACC) volume. Analyses revealed differential type and timing-specific effects of ACE on stress sensitive brain structures: Amygdala and hippocampal volume were affected by ACE severity during a period covering preadolescence and early adolescence. Crucially, this effect was driven by the severity of neglect.

This study aimed to investigate whether the differences in pain perception between patients with borderline personality disorder (BPD) and healthy subjects (HCs) can be explained by differences in the glutamate/GABA ratio in the posterior insula. In total, 29 BPD patients and 31 HCs were included in the statistical analysis. Mechanical pain sensitivity was experimentally assessed with pinprick stimuli between 32 and 512 mN on a numeric rating scale. The metabolites were measured in the right posterior insula using the MEshcher-GArwood Point-RESolved Spectroscopy sequence for single-voxel magnetic resonance spectroscopy (1H-MRS). The 256- and the 512-mN pinprick stimuli were perceived as significantly less painful by the BPD patient group compared with HCs. No differences were found between groups for the glutamate/GABA ratios. A positive correlation between the glutamate/GABA ratio and the pain intensity ratings to 256- and 512-mN pinpricks could be found in the combined and in the HC group. In the BPD patient group, the correlations between the glutamate/GABA ratio and the pain intensity ratings to 256- and 512-mN pinpricks did not reach significance. In conclusion, the study showed that individual differences in pain perception may in part be explained by the individual glutamate/GABA ratio in the posterior insula. However, this possible mechanism does not explain the differences in pain perception between BPD patients and HCs.

Receiving feedback from neural activity, dubbed neurofeedback, can reinforce brain self-regulation. In a real-time functional magnetic resonance imaging (fMRI) experiment, healthy participants received amygdala neurofeedback via a visual brain-computer interface. The brain response to signals of reward and failure was modeled. In contrast to previous analyses, we take into account feedback that immediately preceded these signals. That means we tested whether responses were modulated while participants observed sequent reward and failure signals. The orbitofrontal cortex (OFC) showed a negative Blood Oxygenation Level Dependent (BOLD) response to failure signals, when they were preceded by more failure signals. When failure signals were preceded by reward, in contrast, the response was less pronounced. The results suggest weighted processing of neurofeedback value in the OFC. Learning to self-regulate the brain with neurofeedback may involve similar neural networks as the learning of goal-directed action., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Accurate and reliable quantification of brain metabolites measured in vivo using 1 H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T 1 -weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Childhood maltreatment, such as severe emotional, physical, and sexual abuse and neglect, has been linked to impulse control problems and dysfunctional emotional coping. In borderline personality disorder (BPD), a history of childhood maltreatment may worsen difficulties in emotion regulation, which may in turn give rise to impulsive behaviours. The aim of this self-report study was to investigate associations between childhood maltreatment severity, emotion regulation difficulties, and impulsivity in women with BPD compared to healthy and clinical controls., Methods: Sixty-one female patients with BPD, 57 clinical controls (CC, women with Attention Deficit Hyperactivity Disorder and/or Substance Use Disorder, without BPD), and 60 female healthy controls (HC) completed self-report scales on childhood trauma (Childhood Trauma Questionnaire, CTQ), difficulties in emotion regulation (Difficulties in Emotion Regulation Scale, DERS), and impulsivity (UPPS Impulsive Behaviour Scale). A conditional process analysis was performed to investigate whether emotion dysregulation statistically mediated the effect of childhood maltreatment severity on impulsivity depending on group (BPD vs. CC vs. HC)., Results: Childhood maltreatment, particularly emotional maltreatment, was positively associated with impulsivity and emotion regulation difficulties across all groups. Difficulties in emotion regulation statistically mediated the effect of childhood maltreatment on impulsivity in BPD, but not in the other groups., Conclusion: In the context of current conceptualizations of BPD and previous research, findings suggest that problems with emotion regulation may be related to a history of childhood maltreatment, which may in turn enhance impulsivity. Targeting emotion dysregulation in psychotherapy and discussing it in relation to childhood maltreatment can help decreasing impulsive behaviors in individuals with BPD. Given the correlational design of our study which does not allow causal conclusions, future studies have to employ prospective, experimental designs and include larger sample sizes to corroborate associations between childhood maltreatment, emotion dysregulation, and impulsivity., Competing Interests: This study has been approved by the Ethics Committee of the Medical Faculty Mannheim of Heidelberg University in 2011 as well as by the Psychology Ethics Committee of Leiden University in 2016 (CEP16-1219/381). All participants were informed about the background of the study and provided informed consent, study participation could be terminated at any time point without negative consequences.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Electroconvulsive therapy (ECT) and depression have been associated with brain volume changes, especially in the hippocampus and the amygdala., Methods: In this retrospective study we collected data from individual pre-post ECT whole brain magnetic resonance imaging scans of depressed patients from six German university hospitals. Gray matter volume (GMV) changes were quantified via voxel-based morphometry in a total sample of 92 patients with major depressive episodes (MDE). Additionally, 43 healthy controls were scanned twice within a similar time interval., Results: Most prominently longitudinal GMV increases occurred in temporal lobe regions. Within specific region of interests we detected significant increases of GMV in the hippocampus and the amygdala. These results were more pronounced in the right hemisphere. Decreases in GMV were not observed. GMV changes did not correlate with psychopathology, age, gender or number of ECT sessions. We ruled out white matter reductions as a possible indirect cause of the detected GMV increase., Conclusion: The present findings support the notion of hippocampus and amygdala modulation following an acute ECT series in patients with MDE. These results corroborate the hypothesis that ECT enables primarily unspecific and regionally dependent neuroplasticity effects to the brain., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Real-time functional magnetic resonance imaging (fMRI) neurofeedback training of amygdala hemodynamic activity directly targets a neurobiological mechanism, which contributes to emotion regulation problems in borderline personality disorder (BPD). However, it remains unknown which outcome measures can assess changes in emotion regulation and affective instability, associated with amygdala downregulation in a clinical trial. The current study directly addresses this question. Twenty-four female patients with a DSM-IV BPD diagnosis underwent four runs of amygdala neurofeedback. Before and after the training, as well as at a six-weeks follow-up assessment, participants completed measures of emotion dysregulation and affective instability at diverse levels of analysis (verbal report, clinical interview, ecological momentary assessment, emotion-modulated startle, heart rate variability, and fMRI). Participants were able to downregulate their amygdala blood oxygen-dependent (BOLD) response with neurofeedback. There was a decrease of BPD symptoms as assessed with the Zanarini rating scale for BPD (ZAN-BPD) and a decrease in emotion-modulated startle to negative pictures after training. Further explorative analyses suggest that patients indicated less affective instability, as seen by lower hour-to-hour variability in negative affect and inner tension in daily life. If replicated by an independent study, our results imply changes in emotion regulation and affective instability for several systems levels, including behavior and verbal report. Conclusions are limited due to the lack of a control group. A randomized controlled trial (RCT) will be needed to confirm effectiveness of the training., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Down-regulation of negative emotions has been shown to reliably inhibit the emotion-modulated startle reflex, but it remains unclear whether the timing of the startle probe influences the quantification of emotion regulation with this measure. Moreover, it is not known whether the degree of startle inhibition corresponds to the subjective attenuation of negative emotions. Therefore, the two main goals of the study were, first, to systematically analyze the effect of probe time on startle inhibition and, second, to explore the association between subjectively perceived down-regulation of arousal and valence and the degree of startle inhibition. We presented negative and neutral pictures to N = 47 participants. Pictures were paired with the instruction to reappraise or to maintain the emotions elicited by these pictures. Probes were delivered at three different times during a 12.5-s regulation phase, and the startle response was measured with electromyography. Valence and arousal ratings were assessed after each trial. Results revealed no significant impact of probe time on startle inhibition during reappraisal. Startle inhibition and perceived down-regulation of arousal were significantly and positively correlated, whereas perceived down-regulation of valence was not. The results provide important implications for future studies in terms of startle probe timing and shed light onto the interpretation of startle inhibition as an indicator of subjective attenuation of negative emotions. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

This study aimed to investigate the relation of GABA and glutamate levels in the posterior insula and mechanical pain sensitivity in healthy subjects. Nineteen healthy female individuals underwent single voxel magnetic resonance spectroscopy (MRS) at 3 T. Metabolites were measured in the right posterior insula using MEGA-PRESS spectral editing. Mechanical pain sensitivity was experimentally assessed with pinprick stimuli on a numeric rating scale. Ratings of perceived intensity of 256 mN and 512 mN pinprick stimuli were negatively correlated with GABA levels and positively with glutamate levels in the posterior insula. Pinprick pain ratings were also positively correlated with the glutamate/GABA ratio. No significant correlation for pinprick stimuli of lower forces than 256 mN was observed. The results of our study support the hypothesis that excitatory and inhibitory neurotransmitter levels and/or the ratio of glutamate/GABA levels in the posterior insula are related to individual differences in pain sensitivity. These results are in line with chronic pain studies, where elevated glutamate/GABA ratios in the insular cortex of patients with chronic pain syndromes were observed., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Brain-computer interfaces provide conscious access to neural activity by means of brain-derived feedback ("neurofeedback"). An individual's abilities to monitor and control feedback are two necessary processes for effective neurofeedback therapy, yet their underlying functional neuroanatomy is still being debated. In this study, healthy subjects received visual feedback from their amygdala response to negative pictures. Activation and functional connectivity were analyzed to disentangle the role of brain regions in different processes. Feedback monitoring was mapped to the thalamus, ventromedial prefrontal cortex (vmPFC), ventral striatum (VS), and rostral PFC. The VS responded to feedback corresponding to instructions while rPFC activity differentiated between conditions and predicted amygdala regulation. Control involved the lateral PFC, anterior cingulate, and insula. Monitoring and control activity overlapped in the VS and thalamus. Extending current neural models of neurofeedback, this study introduces monitoring and control of feedback as anatomically dissociated processes, and suggests their important role in voluntary neuromodulation., (© 2018 Wiley Periodicals, Inc.)

Autobiographical memory deficits are known in depression. The temporal distribution thereof across periods of life has rarely been considered yet. Autobiographical memories for 5 life periods were investigated in 27 depressed in-patients and compared to 31 matched healthy controls using the Bielefelder Autobiographisches Gedächtnis Inventar. Depressed patients reported significantly less details in memories dating from childhood to 30 years, correlating with severity of depression. Memories from childhood and recent periods were less positive in depressed patients. Thus, we found a distinct pattern of autobiographical memory deficits in depressed patients. Possible etiological factors, however, need further investigations., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: Platelet transfusion is an effective option to reverse platelet inhibition in thienopyridine-treated patients suffering from bleedings or requiring urgent surgery. However, in ticagrelor-treated patients, the previous studies revealed significant clinical effects to platelet rich plasma (PRP) but poor response to pooled platelets (PP) as used in clinical routine. The aim of this study was to elucidate a potential pathomechanism to explain the poor response of ticagrelor to PP., Methods and Results: From 79 whole blood samples of patients treated with ticagrelor, prasugrel, or clopidogrel, the PRI-VASP was determined before and after in vitro platelet supplementation of PP or PRP at increasing concentrations. Compared to prasugrel- and clopidogrel-treated patients, the PRI-VASP of ticagrelor-treated patients showed no significant increase after in vitro administration of PP. PRI-VASP was performed in ticagrelor-treated samples after in vitro addition of 1: centrifuged PRP platelets resuspended in PP buffer, 2: PP with human serum, 3: human serum alone. Surprisingly, PP with human serum or human serum alone were able to significantly increase PRI-VASP in samples of ticagrelor-treated patients (11.7 ± 10.9 → 61.3 ± 10.9%, p = 0.006; 11.7 ± 10.9 → 54.1 ± 2.7%, p < 0.001). This effect could also be shown using human albumin (18.9 ± 5.1% → 80 g/l human albumin: 48.1 ± 8.3%, p < 0.001)., Conclusion: The present study demonstrates that addition of human serum and human albumin alone is able to reverse the ticagrelor effects in vitro and supports our novel hypothesis of the importance of proteins in reversing the effects of ticagrelor by binding active ticagrelor.

Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter γ-aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA-edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within-site, while site-level differences accounted for comparatively more variance (20%) than vendor-level differences (8%). For MM-suppressed GABA data, the variance was distributed equally between site- (50%) and participant-level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The impact of stress on anger and aggression in Borderline Personality Disorder (BPD) and Attention Deficit Hyperactivity Disorder (ADHD) has not been thoroughly investigated. The goal of this study was to investigate different aspects of anger and aggression in patients with these disorders., Methods: Twenty-nine unmedicated female BPD patients, 28 ADHD patients and 30 healthy controls (HC) completed self-reports measuring trait anger, aggression and emotion regulation capacities. A modified version of the Point Subtraction Aggression Paradigm and a state anger measurement were applied under resting and stress conditions. Stress was induced by the Mannheim Multicomponent Stress Test (MMST)., Results: Both patient groups scored significantly higher on all self-report measures compared to HCs. Compared to ADHD patients, BPD patients reported higher trait aggression and hostility, a stronger tendency to express anger when provoked and to direct anger inwardly. Furthermore, BPD patients exhibited higher state anger than HCs and ADHD patients under both conditions and showed a stress-dependent anger increase. At the behavioral level, no significant effects were found. In BPD patients, aggression and anger were positively correlated with emotion regulation deficits., Conclusions: Our findings suggest a significant impact of stress on self-perceived state anger in BPD patients but not on aggressive behavior towards others in females with BPD or ADHD. However, it appears to be pronounced inwardly directed anger which is of clinical importance in BPD patients.

Impulsivity often develops from disturbed inhibitory control, a function mainly regulated by γ-Aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC) and the fronto-striatal system. In this study, we combined MRS GABA measurements and fMRI to investigate neurochemical and neurofunctional correlates of interference inhibition, further emphasizing the direct relationship between those two systems, as well as their relations to impulsivity in patients with BPD. In addition to BOLD activation, task-dependent functional connectivity was assessed by a generalized psychophysiological interactions approach. Full factorial analyses were performed via SPM to examine the main effect (within-group associations) as well as the interaction term (group differences in the association slope). The UPPS scales were used to evaluate impulsivity traits. Compared to healthy controls (HCs), BPD patients exhibited significantly less ACC-caudate functional connectivity during interference inhibition. ACC GABA levels in BPD patients but not in HCs were positively related to the magnitude of activation in several fronto-striatal regions (e.g. ACC, frontal regions, putamen, caudate,) and the strength of ACC-caudate functional connectivity during interference inhibition. The strength of the correlations of GABA with connectivity significantly differs between the two groups. Moreover, among all the UPPS impulsivity subscales, UPPS sensation seeking in the BPD group was related to GABA and was also negatively related to the task-dependent BOLD activation and functional connectivity in the fronto-striatal network. Finally, mediation analyses revealed that the magnitude of activation in the caudate and the strength of ACC-caudate functional connectivity mediated the relationship between ACC GABA levels and UPPS sensation seeking in patients with BPD. Our findings suggest a disconnectivity of the fronto-striatal network in BPD patients during interference inhibition, particularly for patients with higher impulsivity. The ACC GABAergic system seems to play a crucial role in regulating regional BOLD activations and functional connectivity in this network, which are further associated with impulsive sensation seeking in BPD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Both chronic alcohol consumption and alcohol withdrawal lead to neural tissue damage which partly recovers during abstinence. This study investigated withdrawal-associated changes in glutamatergic compounds, markers of neuronal integrity, and gray matter volumes during acute alcohol withdrawal in the hippocampus, a key region in development and maintenance of alcohol dependence in humans and rats., Methods: Alcohol-dependent patients (N = 39) underwent magnetic resonance imaging (MRI) and MR spectroscopy (MRS) measurements within 24 hours after the last drink and after 2 weeks of abstinence. MRI and MRS data of healthy controls (N = 34) were acquired once. Our thorough quality criteria resulted in N = 15 available spectra from the first and of N = 21 from the second measurement in patients, and of N = 19 from healthy controls. In a translational approach, chronic intermittent ethanol-exposed rats and respective controls (8/group) underwent 5 MRS measurements covering baseline, intoxication, 12 and 60 hours of withdrawal, and 3 weeks of abstinence., Results: In both species, higher levels of markers of glutamatergic metabolism were associated with lower gray matter volumes in the hippocampus in early abstinence. Trends of reduced N-acetylaspartate levels during intoxication persisted in patients with severe alcohol withdrawal symptoms over 2 weeks of abstinence. We observed a higher ratio of glutamate to glutamine during alcohol withdrawal in our animal model., Conclusions: Due to limited statistical power, we regard the results as preliminary and discuss them in the framework of the hypothesis of withdrawal-induced hyperglutamatergic neurotoxicity, alcohol-induced neural changes, and training-associated effects of abstinence on hippocampal tissue integrity., (Copyright © 2017 by the Research Society on Alcoholism.)