Monosynaptic Hippocampal-Prefrontal Projections Contribute to Spatial Memory Consolidation in Mice.

Time locking between neocortical sleep slow oscillations, thalamo-cortical spindles, and hippocampal sharp-wave ripples has convincingly been shown to be a key element of systems consolidation. Here we investigate the role of monosynaptic projections from ventral/intermediate hippocampus to medial prefrontal cortex (mPFC) in sleep-dependent memory consolidation in male mice. Following acquisition learning in the Barnes maze, we optogenetically silenced the axonal terminals of hippocampal projections within mPFC during slow-wave sleep. This silencing during SWS selectively impaired recent but not remote memory in the absence of effects on error rate and escape latencies. Furthermore, it prevented the development of the most efficient search strategy and sleep spindle time-locking to slow oscillation. An increase in post-learning sleep sharp-wave ripple (SPWR) density and reduced time locking of learning-associated SPWR activity to sleep spindles may be a less specific response. Our results demonstrate that monosynaptic projections from hippocampus to mPFC contribute to sleep-dependent memory consolidation, potentially by affecting the temporal coupling of sleep-associated electrophysiological events.SIGNIFICANCE STATEMENT Convincing evidence supports the role of slow-wave sleep (SWS), and the relevance of close temporal coupling of neuronal activity between brain regions for systems consolidation. Less attention has been paid so far to the specific neuronal pathways underlying these processes. Here, we optogenetically silenced the direct monosynaptic projection from ventral/intermediate hippocampus (HC) to medial prefrontal cortex (mPFC) during SWS in male mice following repeated learning trials in a weakly aversive spatial task. Our results confirm the concept that the monosynaptic projection between HC and mPFC contributes to memory consolidation and support an important functional role of this pathway in shaping the temporal precision among sleep-associated electrophysiological events.

Prognostic potential of automated Ki67 evaluation in breast cancer: different hot spot definitions versus true global score.

PURPOSE: The proliferation-associated biomarker Ki67 has potential utility in breast cancer, including aiding decisions based on prognosis, but has unacceptable inter- and intralaboratory variability. The aim of this study was to compare the prognostic potential for Ki67 hot spot scoring and global scoring using different digital image analysis (DIA) platforms. METHODS: An ER+/HER2- breast cancer cohort (n = 139) with whole slide images of sequential sections stained for hematoxylin-eosin, pancytokeratin and Ki67, was analyzed using two DIA platforms. For hot spot analysis virtual dual staining was applied, aligning pancytokeratin and Ki67 images and 22 hot spot algorithms with different features were designed. For global Ki67 scoring an automated QuPath algorithm was applied on Ki67-stained whole slide images. Clinicopathological data included overall survival (OS) and recurrence-free survival (RFS) along with PAM50 molecular subtypes. RESULTS: We show significant variations in Ki67 hot spot scoring depending on number of included tumor cells, hot spot size, shape and location. The higher the number of scored tumor cells, the higher the reproducibility of Ki67 proliferation values. Hot spot scoring had greater prognostic potential for RFS in high versus low Ki67 subgroups (hazard ratio (HR) 6.88, CI 2.07-22.87, p = 0.002), compared to global scoring (HR 3.13, CI 1.41-6.96, p = 0.005). Regarding OS, global scoring (HR 7.46, CI 2.46-22.58, p < 0.001) was slightly better than hot spot scoring (HR 6.93, CI 1.61-29.91, p = 0.009). In adjusted multivariate analysis, only global scoring was an independent prognostic marker for both RFS and OS. In addition, global Ki67-based surrogate subtypes reached higher concordance with PAM50 molecular subtype for luminal A and B tumors (66.3% concordance rate, κ = 0.345), than using hot spot scoring (55.8% concordance rate, κ = 0.250). CONCLUSIONS: We conclude that the automated global Ki67 scoring is feasible and shows clinical validity, which, however, needs to be confirmed in a larger cohort before clinical implementation.

[Assisting the Forgotten Ones - Interventions for Children of Parents with Psychological Disorders]. / Nicht von schlechten Eltern ­ Interventionen und Hilfsangebote für Kinder psychisch kranker Eltern.

Assisting the Forgotten Ones - Interventions for Children of Parents with Psychological Disorders Mental diseases are associated with high levels of distress in various areas of life for those, who are affected. Taking a closer look at the social circumstances, not exclusively the people themselves but also their family members are affected, especially children. In adult treatment these children are often neglected, even if they have a higher risk of suffering a mental illness themselves. A huge amount of this risk is related to the special family environment children are often exposed to right after birth. We already find prevention programs helping these children and their parents to protect their mental health. These programs largely differ regarding parental psychopathology, setting or intensity. This article gives an overview of the special circumstances these children may be confronted with and hence derivates possible starting points to support affected families. A few existing programs will be described in detail. Empirical findings presented in the article give hope for the effectiveness of already existing programs and besides highlight the need for further research and changes in the care system.

Contributions of dopaminergic and non-dopaminergic neurons to VTA-stimulation induced neurovascular responses in brain reward circuits.

Mapping the activity of the human mesolimbic dopamine system by BOLD-fMRI is a tempting approach to non-invasively study the action of the brain reward system during different experimental conditions. However, the contribution of dopamine release to the BOLD signal is disputed. To assign the actual contribution of dopaminergic and non-dopaminergic VTA neurons to the formation of BOLD responses in target regions of the mesolimbic system, we used two optogenetic approaches in rats. We either activated VTA dopaminergic neurons selectively, or dopaminergic and mainly glutamatergic projecting neurons together. We further used electrical stimulation to non-selectively activate neurons in the VTA. All three stimulation conditions effectively activated the mesolimbic dopaminergic system and triggered dopamine releases into the NAcc as measured by in vivo fast-scan cyclic voltammetry. Furthermore, both optogenetic stimulation paradigms led to indistinguishable self-stimulation behavior. In contrast to these similarities, however, the BOLD response pattern differed greatly between groups. In general, BOLD responses were weaker and sparser with increasing stimulation specificity for dopaminergic neurons. In addition, repetitive stimulation of the VTA caused a progressive decoupling of dopamine release and BOLD signal strength, and dopamine receptor antagonists were unable to block the BOLD signal elicited by VTA stimulation. To exclude that the sedation during fMRI is the cause of minimal mesolimbic BOLD in response to specific dopaminergic stimulation, we repeated our experiments using CBF SPECT in awake animals. Again, we found activations only for less-specific stimulation. Based on these results we conclude that canonical BOLD responses in the reward system represent mainly the activity of non-dopaminergic neurons. Thus, the minor effects of projecting dopaminergic neurons are concealed by non-dopaminergic activity, a finding which highlights the importance of a careful interpretation of reward-related human fMRI data.

Digital image analysis of Ki67 in hot spots is superior to both manual Ki67 and mitotic counts in breast cancer.

AIMS: During pathological examination of breast tumours, proliferative activity is routinely evaluated by a count of mitoses. Adding immunohistochemical stains of Ki67 provides extra prognostic and predictive information. However, the currently used methods for these evaluations suffer from imperfect reproducibility. It is still unclear whether analysis of Ki67 should be performed in hot spots, in the tumour periphery, or as an average of the whole tumour section. The aim of this study was to compare the clinical relevance of mitoses, Ki67 and phosphohistone H3 in two cohorts of primary breast cancer specimens (total n = 294). METHODS AND RESULTS: Both manual and digital image analysis scores were evaluated for sensitivity and specificity for luminal B versus A subtype as defined by PAM50 gene expression assays, for high versus low transcriptomic grade, for axillary lymph node status, and for prognostic value in terms of prediction of overall and relapse-free survival. Digital image analysis of Ki67 outperformed the other markers, especially in hot spots. Tumours with high Ki67 expression and high numbers of phosphohistone H3-positive cells had significantly increased hazard ratios for all-cause mortality within 10 years from diagnosis. Replacing manual mitotic counts with digital image analysis of Ki67 in hot spots increased the differences in overall survival between the highest and lowest histological grades, and added significant prognostic information. CONCLUSIONS: Digital image analysis of Ki67 in hot spots is the marker of choice for routine analysis of proliferation in breast cancer.

[Unwanted Side Effects in Children and Youth Psychotherapy - Introduction and Recommendations]. / Unerwünschte Nebenwirkungen in der Kinder- und Jugendlichenpsychotherapie ­ Eine Einführung und Empfehlungen.

Psychotherapy in children and adolescents is effective, but unwanted effects can occur. Until now, psychotherapy research has neglected this important topic, although children and youths are in need of special protection. Unwanted effects caused by therapy are not systematically investigated and a corresponding conceptualization is missing. The aim of this article is to investigate whether the current classifications of unwanted effects of psychotherapy in adults are applicable to children and adolescents and to identify distinctive features. Furthermore, the adaptation of the Inventory for the Assessment of Negative Effects of Psychotherapy for children and adolescents (Children-INEP) is presented. Finally, steps for the information and prevention of unwanted, and negative effects of psychotherapy in children and adolescents are pointed out.

Quantitative tumor heterogeneity assessment on a nuclear population basis.

Immunohistochemistry Ki-67 stain is widely used for visualizing cell proliferation. The common method for scoring the proliferation is to manually select and score a hot spot. This method is time-consuming and will often not give reproducible results due to subjective selection of the hotspots and subjective scoring. An automatic hotspot detection and proliferative index scoring would be time-saving, make the determination of the Ki-67 score easier and minimize the uncertainty of the score by introducing a more objective and standardized score. Tissue Micro Array cores stained for Ki-67 and their neighbor slide stained for Pan Cytokeratin were aligned and Ki-67 positive and negative nuclei were identified inside tumor regions. A heatmap was calculated based on these and illustrates the distribution of the heterogenous response of Ki-67 positive nuclei in the tumor tissue. An automatic hot spot detection was developed and the Ki-67 score was calculated. All scores were compared with scores provided by a pathologist using linear regression models. No significant difference was found between the Ki-67 scores guided by the developed heatmap and the scores provided by a pathologist. For comparison, scores were also calculated at a random place outside the hot spot and these scores were found to be significantly different from the pathologist scores. A heatmap visualizing the heterogeneity in tumor tissue expressed by Ki-67 was developed and used for an automatic identification of hot spots in which a Ki-67 score was calculated. The Ki-67 scores did not differ significantly from scores provided by a pathologist. © 2017 International Society for Advancement of Cytometry.

Digital image analysis outperforms manual biomarker assessment in breast cancer.

In the spectrum of breast cancers, categorization according to the four gene expression-based subtypes 'Luminal A,' 'Luminal B,' 'HER2-enriched,' and 'Basal-like' is the method of choice for prognostic and predictive value. As gene expression assays are not yet universally available, routine immunohistochemical stains act as surrogate markers for these subtypes. Thus, congruence of surrogate markers and gene expression tests is of utmost importance. In this study, 3 cohorts of primary breast cancer specimens (total n=436) with up to 28 years of survival data were scored for Ki67, ER, PR, and HER2 status manually and by digital image analysis (DIA). The results were then compared for sensitivity and specificity for the Luminal B subtype, concordance to PAM50 assays in subtype classification and prognostic power. The DIA system used was the Visiopharm Integrator System. DIA outperformed manual scoring in terms of sensitivity and specificity for the Luminal B subtype, widely considered the most challenging distinction in surrogate subclassification, and produced slightly better concordance and Cohen's κ agreement with PAM50 gene expression assays. Manual biomarker scores and DIA essentially matched each other for Cox regression hazard ratios for all-cause mortality. When the Nottingham combined histologic grade (Elston-Ellis) was used as a prognostic surrogate, stronger Spearman's rank-order correlations were produced by DIA. Prognostic value of Ki67 scores in terms of likelihood ratio χ(2) (LR χ(2)) was higher for DIA that also added significantly more prognostic information to the manual scores (LR-Δχ(2)). In conclusion, the system for DIA evaluated here was in most aspects a superior alternative to manual biomarker scoring. It also has the potential to reduce time consumption for pathologists, as many of the steps in the workflow are either automatic or feasible to manage without pathological expertise.

SPECT-imaging of activity-dependent changes in regional cerebral blood flow induced by electrical and optogenetic self-stimulation in mice.

Electrical and optogenetic methods for brain stimulation are widely used in rodents for manipulating behavior and analyzing functional connectivities in neuronal circuits. High-resolution in vivo imaging of the global, brain-wide, activation patterns induced by these stimulations has remained challenging, in particular in awake behaving mice. We here mapped brain activation patterns in awake, intracranially self-stimulating mice using a novel protocol for single-photon emission computed tomography (SPECT) imaging of regional cerebral blood flow (rCBF). Mice were implanted with either electrodes for electrical stimulation of the medial forebrain bundle (mfb-microstim) or with optical fibers for blue-light stimulation of channelrhodopsin-2 expressing neurons in the ventral tegmental area (vta-optostim). After training for self-stimulation by current or light application, respectively, mice were implanted with jugular vein catheters and intravenously injected with the flow tracer 99m-technetium hexamethylpropyleneamine oxime (99mTc-HMPAO) during seven to ten minutes of intracranial self-stimulation or ongoing behavior without stimulation. The 99mTc-brain distributions were mapped in anesthetized animals after stimulation using multipinhole SPECT. Upon self-stimulation rCBF strongly increased at the electrode tip in mfb-microstim mice. In vta-optostim mice peak activations were found outside the stimulation site. Partly overlapping brain-wide networks of activations and deactivations were found in both groups. When testing all self-stimulating mice against all controls highly significant activations were found in the rostromedial nucleus accumbens shell. SPECT-imaging of rCBF using intravenous tracer-injection during ongoing behavior is a new tool for imaging regional brain activation patterns in awake behaving rodents providing higher spatial and temporal resolutions than 18F-2-fluoro-2-dexoyglucose positron emission tomography.

Wave propagation of cortical population activity under urethane anesthesia is state dependent.

BACKGROUND: Propagating waves of excitation have been observed extensively in the neocortex, during both spontaneous and sensory-evoked activity, and they play a critical role in spatially organizing information processing. However, the state-dependence of these spatiotemporal propagation patterns is largely unexplored. In this report, we use voltage-sensitive dye imaging in the rat visual cortex to study the propagation of spontaneous population activity in two discrete cortical states induced by urethane anesthesia. RESULTS: While laminar current source density patterns of spontaneous population events in these two states indicate a considerable degree of similarity in laminar networks, lateral propagation in the more active desynchronized state is approximately 20% faster than in the slower synchronized state. Furthermore, trajectories of wave propagation exhibit a strong anisotropy, but the preferred direction is different depending on cortical state. CONCLUSIONS: Our results show that horizontal wave propagation of spontaneous neural activity is largely dependent on the global activity states of local cortical circuits.

Noninvasive monitoring of stroke volume with resynchronization devices in patients with ischemic cardiomyopathy.

BACKGROUND: A novel method to estimate cardiac volumes based on impedance measurements using the leads of a resynchronization device has been developed. This study investigated the method in patients with ischemic cardiomyopathy and documented wall motion abnormalities. METHOD AND RESULTS: Fifteen postinfarction patients (age 68 ± 8 years, ejection fraction 27 ± 5%) with symptomatic heart failure and ≥ 1 akinetic or dyskinetic segment were included. During the implantation of a cardiac resynchronization therapy (CRT) device, acute impedance curves were recorded along with stroke volume determined by the arterial pulse contour method. In an overdrive protocol, the impedance parameter "stroke impedance" decreased in significant correlation with stroke volume in all patients. The median correlation coefficient between stroke volume and stroke impedance was 0.83 (interquartile range 0.70-0.89). Furthermore, the atrioventricular delay was optimized based on impedance and reference stroke volume. After optimization by the impedance method, it differed by 18 ± 15 ms from the figure after optimization by the invasive reference. Compared with a standard atrioventricular delay of 120 ms, stroke volume was improved by 8.6 ± 9.8% with the use of invasive optimization and by 6.4 ± 10.8% with the use of impedance-based optimization. CONCLUSIONS: In CRT patients with chronic infarction and wall motion abnormalities, impedance is a valid parameter to estimate stroke volume and to guide optimization of CRT timing.

Recalling gist memory depends on CA1 hippocampal neurons for lifetime retention and CA3 neurons for memory precision.

Why some of us remember events more clearly than others and why memory loses precision over time is a major focus in memory research. Here, we show that the recruitment of specific neuroanatomical pathways within the medial temporal lobe (MTL) of the brain defines the precision of the memory recalled over the lifespan. Using optogenetics, neuronal activity mapping, and studying recent to very remote memories, we report that the hippocampal subfield CA1 is necessary for retrieving the gist of events and receives maximal support from MTL cortical areas (MEC, LEC, PER, and POR) for recalling the most remote memories. In contrast, reduction of CA3's activity alone coincides with the loss of memory precision over time. We propose that a shift between specific MTL subnetworks over time might be a fundamental mechanism of memory consolidation.

Bochum Assessment of Avoidance-based Emotion Regulation for Children (BAER-C): Development and evaluation of a new instrument measuring anticipatory avoidance-based emotion regulation in anxiety eliciting situations.

Avoidance-based emotion regulation plays a central role in the development and maintenance of anxiety disorders across the life span. However, measures for children that account for different avoidance strategies, are scarce. Derived from Gross' Process Model of Emotion Regulation, the Bochum Assessment of Avoidance-based Emotion Regulation for Children (BAER-C) was developed to assess avoidance strategies (cognitive avoidance, behavioural avoidance, verbal reassurance, and social reassurance) and reappraisal in anticipatory anxious situations. In the present study, the BAER-C was administered to 129 school children aged 8 to 14 and 199 children with anxiety disorders aged 8 to 16 and their parents, along with established measures on anxiety, psychopathology, and emotion regulation. Factor structure, internal consistency, convergent, divergent and construct validity were analysed. Results of the anxious sample showed a satisfactory internal consistency (McDonald's ω = .94) for all scales as well as positive correlations with anxiety symptoms (all rs > .17, all ps < .05). Factor analysis supported a five-factor model. This model was confirmed in the student sample. Children with an anxiety disorder scored higher on behavioural avoidance, verbal reassurance, and social reassurance than school children (F (5,304) = 12.63, p = .003, ηp2 = .17). Results for construct validity were ambiguous. Our analyses suggest that the BAER-C is a promising theory-based new instrument to reliably assess different avoidance strategies in children. More research is needed to further analyse construct validity with other emotion regulation questionnaires.

Measuring extinction learning across the lifespan - Adaptation of an optimized paradigm to closely match exposure treatment procedures.

Here, we tested the feasibility of a new paradigm developed to investigate the mechanisms of exposure-therapy. The protocol was previously developed for the use with adults and optimized to closely model the mechanisms underlying exposure, i.e. extinction learning. We adapted this paradigm for the use with children, and tested its feasibility in children and adult participants. We used an aversive acoustic unconditioned stimulus (US), picture-based rating scales and a child-oriented instruction/practice procedure. Results indicate robust fear acquisition, extinction and reinstatement on a self-report (US-expectancy) and on a physiological (startle reflex) level. We found evidence for the paradigms sensitivity to age and anxiety-dependent individual differences in fear-learning and extinction. We conclude that the present paradigm is capable of modeling the key mechanisms of exposure-therapy, that is extinction-learning, and can be accomplished with children, adolescents and adults, rendering it promising to bridge the gap between experimental protocols and treatment across the lifespan.

TetrODrive: an open-source microdrive for combined electrophysiology and optophysiology.

Objective. In tetrode recordings, the cell types of the recorded units are difficult to determine based on electrophysiological characteristics alone. Optotagging, the use of optogenetic stimulation to precisely identify cells, is a method to overcome this challenge. However, recording from many different cells requires advancing electrodes and light sources slowly through the brain with a microdrive. Existing designs suffer from a number of drawbacks, such as limited stability and precision, high cost, complex assembly, or excessive size and weight.Approach. We designed TetrODrive as a microdrive that can be 3D printed on an inexpensive desktop resin printer, has minimal parts, assembly time, and cost. The microdrive can be assembled in 15 min and the price for all materials, including the 3D printer, is lower than a single commercial microdrive. To maximize recording stability, we mechanically decoupled the drive mechanism from the electrical and optical connectors.Main results. The developed microdrive is small and light enough (<1.5 g) to be carried effortlessly by a mouse. It allows reliable recordings from single units and optogenetically identified units, even across recording sessions. In contrast to previous designs, it provides a decoupling of plugging forces from the main drive body for enhanced stability. Owing to its moveable optical fiber, our microdrive can also be used for fiber photometry. The cost of a single drive is below 20 €. We evaluated our microdrive by recording single units and calcium signals in the ventral tegmental area of mice and confirmed cell identity via optotagging. Thereby we found units not following the classical reward prediction error model.Significance. TetrODrive is a tiny, lightweight, and affordable microdrive for optophysiology in mice. Its open design, price, and built-in characteristics can significantly expand the use of microdrives in mice.

Personalized Assessment of Anxiety and Avoidance in Children and Their Parents-Development and Evaluation of the Anxiety and Avoidance Scale for Children.

In treating childhood anxiety disorders, therapists use highly individualized anxiety hierarchies to assess anxiety-eliciting situations and to personalize treatment. In contrast, psychometric assessment of anxiety symptoms in children usually consists of standardized questionnaires, assessing either total anxiety or disorder-specific symptom scores, prioritizing comparability over individual information. To account for interindividual differences, the Anxiety and Avoidance Scale for Children (AVAC) was developed, following a precise, personalized, assessment approach. In responding to the questionnaire, children and parents identify the most anxiety-eliciting situations before starting treatment, and rate them for anxiety and avoidance. Ratings are repeated over the course of treatment. The aim of this study is to introduce the new questionnaire and present first data on psychometric properties. The AVAC was administered to 389 children with separation anxiety disorder (N = 148), social anxiety disorder (N = 110) or specific phobia (N = 131) aged 8 to 16 and their parents, along with other measures of anxiety and psychopathology before and after cognitive behavioral treatment. Results showed adequate to good test-retest reliability. The AVAC items correlated significantly with established anxiety questionnaires, indicating convergent construct validity. Regarding divergent construct validity, the AVAC showed only small correlations with externalizing symptoms, demonstrating its precision in measuring anxiety and avoidance. The questionnaire was also sensitive to change after treatment, with medium to large effects in the reduction of anxiety and avoidance. The present analyses suggest that the new personalized assessment approach with the AVAC is a reliable and valid assessment of individualized anxiety and avoidance, as well as change in those constructs over the course of CBT treatment.

Resynchronization therapy optimization by intracardiac impedance.

AIMS: For successful cardiac resynchronization therapy (CRT), an optimization of left ventricular (LV) lead position and stimulation timing is required. The feasibility of optimizing LV lead position, atrioventricular delay (AVd), and interventricular delay (VVd) in CRT using intracardiac impedance measurement was evaluated. METHODS AND RESULTS: Heart failure patients (n = 14, NYHA 13×III, 1×II, ejection fraction: 26 ± 6%, QRS: 165 ± 30 ms) were stimulated by AAI and biventricular (DDD-BiV) pacing in turn. Left ventricular lead site, AVd, and VVd were varied. An external pacemaker measured impedance, and a micromanometer catheter measured LV and aortic pressure. Left ventricular dP/dt(max), pulse pressure (PP), stroke volume (SV), end-systolic impedance (ESZ), and stroke impedance (SZ) were determined. Optimization results achieved by maximum increase in PP, SV, SZ, or ESZ were compared with the reference method (dP/dt(max) increase). Left ventricular lead site variation resulted in a mean optimal dP/dt(max) benefit of 18.2%. Lead site selection by SZ/PP/SV showed benefits of 17.4/17.9/17.2%, respectively. Atrioventricular delay optimization increased the optimal benefit to 22.1%, the methods ESZ/PP/SV achieved 20.1/20.8/19.4%. Interventricular delay optimization resulted in a benefit of 19.1/19.4/19.9% (SZ/PP/SV) with an optimum of 21.8%. The achieved benefit did not differ significantly between impedance, SV, and PP methods. A significant correlation between AVd values selected by dP/dt(max) and by the other methods was observed (r = 0.75/0.67/0.60 for ESZ/PP/SV). CONCLUSION: The feasibility of optimizing LV lead site, AVd, and VVd by intracardiac impedance has been demonstrated for CRT patients with a similar performance as using SV and PP. Application of intracardiac impedance for automatic implant-based CRT optimization appears to be within reach.

Intracardiac impedance monitors stroke volume in resynchronization therapy patients.

AIMS: Monitoring of haemodynamic parameters or surrogate parameters of the left ventricle is especially important for patients under cardiac resynchronization therapy (CRT). Intracardiac impedance reflects left ventricular (LV) volume changes well in animal models. Since it is unknown whether this also holds in humans with heart failure (HF), we examined the correlation of LV intracardiac impedance with haemodynamic parameters in CRT patients for different positions of the LV lead. METHODS AND RESULTS: In 14 HF patients with non-ischaemic cardiomyopathy (four female, age 70 +/- 6 years, NYHA 2.9 +/- 0.3, EF 26 +/- 6%), one or two suitable implantation sites for the LV lead were selected. Following atrial, right ventricular, and LV catheter positioning, a micro-manometer catheter was placed in the ascending aorta. Surface ECG, impedance, and aortic pressure were recorded during graded overdrive bi-ventricular pacing in DDD mode. The correlation between impedance and stroke volume (SV) or pulse pressure (PP) changes was compared for different LV lead positions. In total, 20 overdrive pacing tests were performed at six different LV lead positions. Strong correlations were found between stroke impedance (SZ) and SV (R = 0.82 +/- 0.16) as well as between SZ and PP (R = 0.81 +/- 0.16) without significant influence of LV lead position. CONCLUSION: In HF patients, a strong correlation between changes in intracardiac impedance and LV SV was found. Typical LV lead implant positions have been tested and all appear to be suitable for this method of LV volume monitoring.

The role of exposure in the treatment of anxiety in children and adolescents: protocol of a systematic review and meta-analysis.

BACKGROUND: In children and adolescents, anxiety disorders (ADs) are among the most prevalent mental disorders. While there is a solid empirical foundation to support CBT as an evidence-based treatment for childhood ADs, the mechanisms underlying the efficacy of CBT are not well explored. Exposure is assumed to be vital to the efficacy of CBT in ADs, but empirical evidence (e.g., dismantling studies) showing that exposure is indeed a vital element of effective treatments is relatively scarce. The proposed meta-analysis aims to investigate the role of exposure in reducing symptoms of anxiety among children and adolescents. METHODS: A systematic search of several electronic databases including PubMed/MEDLINE, PsycINFO, Psyndex plus, Web of Science, Scopus, and EMBASE will be conducted (from inception onwards). We will include randomized and non-randomized clinical trials examining exposure and anxiety among children and adolescents. If feasible, we will also include experimental, quasi-experimental, and observational studies. The primary outcome will be improvement in anxiety levels (recovery or change in anxiety rating scale) after exposure. Three reviewers will independently screen all citations, abstract data, and full-text articles. The methodological quality (or risk of bias) of individual studies will be appraised using an appropriate tool. If feasible, we will conduct mixed effects meta-analysis. Additional analyses will be conducted to explore the potential sources of heterogeneity (e.g., dose of exposure, age group, methodological quality). DISCUSSION: This systematic review and meta-analysis will examine the role of exposure in reducing symptoms of anxiety among youth. The review will provide information on the working mechanisms underlying the efficacy of CBT. Our findings will be of interest to mental health professionals, researchers, and policy makers who wish to support children and adolescents with anxiety disorders by guiding well-informed treatment decisions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (CRD42019128667).

An optically transparent multi-electrode array for combined electrophysiology and optophysiology at the mesoscopic scale.

OBJECTIVE: A number of tissue penetrating opto-electrodes to simultaneously record and optogenetically influence brain activity have been developed. For experiments at the surface of the brain, such as electrocorticogram (ECoG) recordings and surface optogenetics, fewer devices have been described and no device has found widespread adoption for neuroscientific experiments. One issue slowing adoption is the complexity and fragility of existing devices, typically based on transparent electrode materials like graphene and indium-tin oxide (ITO). We focused here on improving existing processes based on metal traces and polyimide (PI), which produce more robust and cost-effective devices, to develop a multi-electrode array for optophysiology. APPROACH: The most widely used substrate material for surface electrodes, PI, has seen little use for optophysiologicalµECoG/ECoG arrays. This is due to its lack of transparency at optogenetically relevant short wavelengths. Here we use very thin layers of PI in combination with chrome-gold-platinum electrodes to achieve the necessary substrate transparency and high mechanical flexibility in a device that still rejects light artifacts well. MAIN RESULTS: The manufactured surface arrays have a thickness of only 6.5 µm, resulting in 80% transparency for blue light. We demonstrate immunity against opto-electric artifacts, long term stability and biocompatibility as well as suitability for optical voltage imaging. The biocompatible arrays are capable of recording stable ECoGs over months without any measurable degradation and can be used to map the tonotopic organization of the curved rodent auditory cortex. SIGNIFICANCE: Our novel probes combine proven materials and processing steps to create optically near-transparent electrode arrays with superior longevity. In contrast to previous opto-electrodes, our probes are simple to manufacture, robust, offer long-term stability, and are a practical engineering solution for optophysiological experiments not requiring transparency of the electrode sites themselves.