Intolerance of uncertainty predicts fear extinction in amygdala-ventromedial prefrontal cortical circuitry

Background: Coordination of activity between the amygdala and ventromedial prefrontal cortex (vmPFC) is important for fear-extinction learning. Aberrant recruitment of this circuitry is associated with anxiety disorders. Here, we sought to determine if individual differences in future threat uncertainty sensitivity, a potential risk factor for anxiety disorders, underly compromised recruitment of fear extinction circuitry. Twenty-two healthy subjects completed a cued fear conditioning task with acquisition and extinction phases. During the task, pupil dilation, skin conductance response, and functional magnetic resonance imaging were acquired. We assessed the temporality of fear extinction learning by splitting the extinction phase into early and late extinction. Threat uncertainty sensitivity was measured using self-reported intolerance of uncertainty (IU). Results: During early extinction learning, we found low IU scores to be associated with larger skin conductance responses and right amygdala activity to learned threat vs. safety cues, whereas high IU scores were associated with no skin conductance discrimination and greater activity within the right amygdala to previously learned safety cues. In late extinction learning, low IU scores were associated with successful inhibition of previously learned threat, reflected in comparable skin conductance response and right amgydala activity to learned threat vs. safety cues, whilst high IU scores were associated with continued fear expression to learned threat, indexed by larger skin conductance and amygdala activity to threat vs. safety cues. In addition, high IU scores were associated with greater vmPFC activity to threat vs. safety cues in late extinction. Similar patterns of IU and extinction learning were found for pupil dilation. The results were specific for IU and did not generalize to self-reported trait anxiety. Conclusions: Overall, the neural and psychophysiological patterns observed here suggest high IU individuals to disproportionately generalize threat during times of uncertainty, which subsequently compromises fear extinction learning. More broadly, these findings highlight the potential of intolerance of uncertainty-based mechanisms to help understand pathological fear in anxiety disorders and inform potential treatment targets

Spectroscopic analysis of finite size effects around a Kondo quantum dot

We consider a simple setup in which a small quantum dot is strongly connected to a finite size box. This box can be either a metallic box or a finite size quantum wire.The formation of the Kondo screening cloud in the box strongly depends on the ratio between the Kondo temperature and the box level spacing. By weakly connecting two metallic reservoirs to the quantum dot, a detailed spectroscopic analysis can be performed. Since the transport channels and the screening channels are almost decoupled, such a setup allows an easier access to the measure of finite-size effects associated with the finite extension of the Kondo cloud.Comment: contribution to Les Houches proceeding, ``Quantum magnetism'' 200

Successful reduction of intraventricular asynchrony is associated with superior response to cardiac resynchronization therapy

<p>Abstract</p> <p>Background</p> <p>Cardiac resynchronization therapy (CRT) is generally associated with a low to moderate increase of the left ventricular ejection fraction (LVEF). In some patients, however, LVEF improves remarkably and reaches near-normal values. The aim of the present study was to further characterize these so called 'super-responders' with a special focus on the extent of intra- and interventricular asynchrony before and after device implantation compared to average responders.</p> <p>Methods</p> <p>37 consecutive patients who underwent CRT device implantation according to current guidelines were included in the study. Patients were examined by echocardiography before, one day after and six months after device implantation. Pre-defined criterion for superior response to CRT was an LVEF increase > 15% after six months.</p> <p>Results</p> <p>At follow-up, eight patients (21.6%) were identified as super-responders. There were no significant differences regarding age, gender, prevalence of ischemic heart disease and LVEF between average and super-responders at baseline. After six months, LVEF had significantly increased from 26.7% ± 5.7% to 33.1% ± 7.9% (<it>p </it>< 0.001) in average and from 24.0% ± 6.7% to 50.3% ± 7.4% (<it>p </it>< 0.001) in super-responders. Both groups showed a significant reduction of QRS duration as well as LV end-diastolic and -systolic volumes under CRT. At baseline, the interventricular mechanical delay (IVMD) was 53.7 ± 20.9 ms in average and 56.9 ± 22.4 ms in super-responders - representing a similar extent of interventricular asynchrony in both groups (<it>p </it>= 0.713). CRT significantly reduced the IVMD to 20.3 ± 15.7 (<it>p </it>< 0.001) in average and to 19.8 ± 15.9 ms (<it>p </it>= 0.013) in super-responders with no difference between both groups (<it>p </it>= 0.858). As a marker for intraventricular asynchrony, we assessed the longest intraventricular delay between six basal LV segments. At baseline, there was no difference between average (86.2 ± 30.5 ms) and super-responders (78.8 ± 23.6 ms, <it>p </it>= 0.528). CRT significantly reduced the longest intraventricular delay in both groups - with a significant difference between average (66.2 ± 36.2 ms) and super-responders (32.5 ± 18.3 ms, <it>p </it>= 0.022). Multivariate logistic regression analysis identified the longest intraventricular delay one day after device implantation as an independent predictor of superior response to CRT (<it>p </it>= 0.038).</p> <p>Conclusions</p> <p>A significant reduction of the longest intraventricular delay correlates with superior response to CRT.</p

The beta-Oslo method: experimentally constrained (n,γn,\gamma) reaction rates relevant to the rr-process

Unknown neutron-capture reaction rates remain a significant source of uncertainty in state-of-the-art $r$-process nucleosynthesis reaction network calculations. As the $r$-process involves highly neutron-rich nuclei for which direct ($n,\gamma$) cross-section measurements are virtually impossible, indirect methods are called for to constrain ($n,\gamma$) cross sections used as input for the $r$-process nuclear network. Here we discuss the newly developed beta-Oslo method, which is capable of providing experimental input for calculating ($n,\gamma$) rates of neutron-rich nuclei. The beta-Oslo method represents a first step towards constraining neutron-capture rates of importance to the $r$-process.Comment: 4 pages, 1 figure, conference proceedings Nuclei in the Cosmos XV 2018, Italy

Enhanced Extinction of Aversive Memories by High-Frequency Stimulation of the Rat Infralimbic Cortex

Electrical stimulation of the rodent medial prefrontal cortex (mPFC), including the infralimbic cortex (IL), immediately prior to or during fear extinction training facilitates extinction memory. Here we examined the effects of high-frequency stimulation (HFS) of the rat IL either prior to conditioning or following retrieval of the conditioned memory, on extinction of Pavlovian fear and conditioned taste aversion (CTA). IL-HFS applied immediately after fear memory retrieval, but not three hours after retrieval or prior to conditioning, subsequently reduced freezing during fear extinction. Similarly, IL-HFS given immediately, but not three hours after, retrieval of a CTA memory reduced aversion during extinction. These data indicate that HFS of the IL may be an effective method for reducing both learned fear and learned aversion

Sequential biventricular pacing improves regional contractility, longitudinal function and dyssynchrony in patients with heart failure and prolonged QRS

<p>Abstract</p> <p>Aims</p> <p>Biventricular pacing (BiP) is an effective treatment in systolic heart failure (HF) patients with prolonged QRS. However, approximately 35% of the patients receiving BiP are classified as non-responders. The aim of this study is to evaluate the acute effects of VV-optimization on systolic heart function.</p> <p>Methods</p> <p>Twenty-one HF patients aged 72 (46-88) years, QRS 154 (120-190) ms, were studied with echocardiography, Tissue Doppler Imaging (TDI) and 3D-echo the first day after receiving a BiP device. TDI was performed; during simultaneous pacing (LV-lead pacing 4 ms before the RV-lead) and during sequential pacing (LV 20 and 40 ms before RV and RV 20 and 40 ms before LV-lead pacing). Systolic heart function was studied by tissue tracking (TT) for longitudinal function and systolic maximal velocity (SMV) for regional contractility and signs of dyssynchrony assessed by time-delays standard deviation of aortic valve opening to SMV, AVO-SMV/SD and tissue synchronization imaging (TSI).</p> <p>Results</p> <p>The TT mean value preoperatively was 4,2 ± 1,5 and increased at simultaneous pacing to 5,0 ± 1,2 mm (p < 0,05), and at best VV-interval to 5,4 ± 1,2 (p < 0,001). Simultaneous pacing achieved better TT distance compared with preoperative in 16 patients (76%). However, it was still higher after VV-optimization in 12 patients 57%. Corresponding figures for SMV were 3,0 ± 0,7, 3,5 ± 0,8 (p < 0,01), and 3,6 ± 0,8 (p < 0,001). Also dyssynchrony improved.</p> <p>Conclusions</p> <p>VV-optimization in the acute phase improves systolic heart function more than simultaneous BiP pacing. Long-term effects should be evaluated in prospective randomized trials.</p

Implementation of seven echocardiographic parameters of myocardial asynchrony to improve the long-term response rate of cardiac resynchronization therapy (CRT)

<p>Abstract</p> <p>Background</p> <p>Cardiac resynchronization Therapy (CRT) is an effective therapy for chronic heart failure with beneficial hemodynamic effects leading to a reduction of morbidity and mortality. The responder rates, however, are low. There are various and contentious echocardiographic parameters of myocardial asynchrony. Patient selection by echocardiographic assessment of asynchrony is thought to improve responder rates.</p> <p>Methods</p> <p>In this small single-center pilot-study, seven established parameters of myocardial asynchrony were used to select patients for CRT: (1) interventricular electromechanical delay (IMD, cut-off ≥ 40 ms), (2) Septal-to-posterior wall motion delay (SPWMD, ≥ 130 ms), (3) maximal difference in time-to-peak velocities between any two of twelve LV segments (Ts-12 ≥ 104 ms), (4) standard deviation of time to peak myocardial velocities (Ts-12-SD, ≥ 34.4 ms), (5) difference between the septal and basal time-to-peak velocity (TDId, ≥ 60 ms), (6) left ventricular electromechanical delay (LVEMD, > 140 ms) and (7) delayed longitudinal contraction (DLC, > 2 segments).</p> <p>16 chronic heart failure patients (NYHA III–IV, LVEF < 0.35, QRS ≥ 120 ms) at least two out of seven parameters of myocardial asynchrony received cardiac resynchronization therapy (CRT-ICD). Follow-up echo examination was after 6 months. The control group was a historic group of CRT patients (n = 38) who had not been screened for echocardiographic signs of myocardial asynchrony prior to device implantation.</p> <p>Results</p> <p>Based on reverse remodeling (relative reduction of LVESV > 15%, relative increase of LVEF > 25%), the responder rate to CRT was 81.2% in patients selected for CRT according to our protocol as compared to 47.4% in the control group (p = 0.04). At baseline, there were on average 4.1 ± 1.6 positive parameters of asynchrony (follow-up: 3.7 [± 1.6] parameters positive, p = 0.52). Only the LVEMD decreased significantly after CRT (p = 0.027). The remaining parameters showed a non-significant trend towards reduction of myocardial asynchrony.</p> <p>Conclusion</p> <p>The implementation of different markers of asynchrony in the selection process for CRT improves the hemodynamic response rate to CRT.</p

Pre-implant right ventricular function might be an important predictor of the response to cardiac resynchronization therapy

<p>Abstract</p> <p>Objective</p> <p>Cardiac resynchronization therapy is proven efficacious in patients with heart failure (HF). Presence of biventricular HF is associated with a worse prognosis than having only left ventricular (LV) HF and pacing might deteriorate heart function. The aim of the study was to assess a possible significance of right ventricular (RV) pre-implant systolic function to predict response to CRT.</p> <p>Design</p> <p>We studied 22 HF-patients aged 72 ± 11 years, QRS-duration 155 ± 20 ms and with an LV ejection fraction (EF) of 26 ± 6% before and four weeks after receiving a CRT-device.</p> <p>Results</p> <p>There were no changes in LV diameters or end systolic volume (ESV) during the study. However, end diastolic volume (EDV) decreased from 226 ± 71 to 211 ± 64 ml (p = 0.02) and systolic maximal velocities (SMV) increased from 2.2 ± 0.4 to 2.6 ± 0.9 cm/s (p = 0.04). Pre-implant RV-SMV (6.2 ± 2.6 cm/s) predicted postoperative increase in LV contractility, p = 0.032.</p> <p>Conclusions</p> <p>Pre-implant decreased RV systolic function might be an important way to predict a poor response to CRT implicating that other treatments should be considered. Furthermore we found that 3D- echocardiography and Tissue Doppler Imaging were feasible to detect short-term changes in LV function.</p

High-Throughput Single-Cell Manipulation in Brain Tissue

The complexity of neurons and neuronal circuits in brain tissue requires the genetic manipulation, labeling, and tracking of single cells. However, current methods for manipulating cells in brain tissue are limited to either bulk techniques, lacking single-cell accuracy, or manual methods that provide single-cell accuracy but at significantly lower throughputs and repeatability. Here, we demonstrate high-throughput, efficient, reliable, and combinatorial delivery of multiple genetic vectors and reagents into targeted cells within the same tissue sample with single-cell accuracy. Our system automatically loads nanoliter-scale volumes of reagents into a micropipette from multiwell plates, targets and transfects single cells in brain tissues using a robust electroporation technique, and finally preps the micropipette by automated cleaning for repeating the transfection cycle. We demonstrate multi-colored labeling of adjacent cells, both in organotypic and acute slices, and transfection of plasmids encoding different protein isoforms into neurons within the same brain tissue for analysis of their effects on linear dendritic spine density. Our platform could also be used to rapidly deliver, both ex vivo and in vivo, a variety of genetic vectors, including optogenetic and cell-type specific agents, as well as fast-acting reagents such as labeling dyes, calcium sensors, and voltage sensors to manipulate and track neuronal circuit activity at single-cell resolution

Muscle fiber-type distribution predicts weight gain and unfavorable left ventricular geometry: a 19 year follow-up study

BACKGROUND: Skeletal muscle consists of type-I (slow-twitch) and type-II (fast-twitch) fibers, with proportions highly variable between individuals and mostly determined by genetic factors. Cross-sectional studies have associated low percentage of type-I fibers (type-I%) with many cardiovascular risk factors. METHODS: We investigated whether baseline type-I% predicts left ventricular (LV) structure and function at 19-year follow-up, and if so, which are the strongest mediating factors. At baseline in 1984 muscle fiber-type distribution (by actomyosin ATPase staining) was studied in 63 healthy men (aged 32–58 years). The follow-up in 2003 included echocardiography, measurement of obesity related variables, physical activity and blood pressure. RESULTS: In the 40 men not using cardiovascular drugs at follow-up, low type-I% predicted higher heart rate, blood pressure, and LV fractional shortening suggesting increased sympathetic tone. Low type-I% predicted smaller LV chamber diameters (P ≤ 0.009) and greater relative wall thickness (P = 0.034) without increase in LV mass (concentric remodeling). This was explained by the association of type-I% with obesity related variables. Type-I% was an independent predictor of follow-up body fat percentage, waist/hip ratio, weight gain in adulthood, and physical activity (in all P ≤ 0.001). After including these risk factors in the regression models, weight gain was the strongest predictor of LV geometry explaining 64% of the variation in LV end-diastolic diameter, 72% in end-systolic diameter, and 53% in relative wall thickness. CONCLUSION: Low type-I% predicts obesity and weight gain especially in the mid-abdomen, and consequently unfavourable LV geometry indicating increased cardiovascular risk