Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline

Learning to predict threat is a fundamental ability of many biological organisms, and a laboratory model for anxiety disorders. Interfering with such memories in humans would be of high clinical relevance. On the basis of studies in cell cultures and slice preparations, it is hypothesised that synaptic remodelling required for threat learning involves the extracellular enzyme matrix metalloproteinase (MMP) 9. However, in vivo evidence for this proposal is lacking. Here we investigate human Pavlovian fear conditioning under the blood-brain barrier crossing MMP inhibitor doxycyline in a pre-registered, randomised, double-blind, placebo-controlled trial. We find that recall of threat memory, measured with fear-potentiated startle 7 days after acquisition, is attenuated by ~60% in individuals who were under doxycycline during acquisition. This threat memory impairment is also reflected in increased behavioural surprise signals to the conditioned stimulus during subsequent re-learning, and already late during initial acquisition. Our findings support an emerging view that extracellular signalling pathways are crucially required for threat memory formation. Furthermore, they suggest novel pharmacological methods for primary prevention and treatment of posttraumatic stress disorder.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.65

Interaction Between Convection and Pulsation

This article reviews our current understanding of modelling convection dynamics in stars. Several semi-analytical time-dependent convection models have been proposed for pulsating one-dimensional stellar structures with different formulations for how the convective turbulent velocity field couples with the global stellar oscillations. In this review we put emphasis on two, widely used, time-dependent convection formulations for estimating pulsation properties in one-dimensional stellar models. Applications to pulsating stars are presented with results for oscillation properties, such as the effects of convection dynamics on the oscillation frequencies, or the stability of pulsation modes, in classical pulsators and in stars supporting solar-type oscillations.Comment: Invited review article for Living Reviews in Solar Physics. 88 pages, 14 figure

Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine.

OBJECTIVE: Circulatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock. METHODS: The European Society of Intensive Care Medicine invited 12 experts to form a Task Force to update a previous consensus (Antonelli et al.: Intensive Care Med 33:575-590, 2007). The same five questions addressed in the earlier consensus were used as the outline for the literature search and review, with the aim of the Task Force to produce statements based on the available literature and evidence. These questions were: (1) What are the epidemiologic and pathophysiologic features of shock in the intensive care unit ? (2) Should we monitor preload and fluid responsiveness in shock ? (3) How and when should we monitor stroke volume or cardiac output in shock ? (4) What markers of the regional and microcirculation can be monitored, and how can cellular function be assessed in shock ? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock ? Four types of statements were used: definition, recommendation, best practice and statement of fact. RESULTS: Forty-four statements were made. The main new statements include: (1) statements on individualizing blood pressure targets; (2) statements on the assessment and prediction of fluid responsiveness; (3) statements on the use of echocardiography and hemodynamic monitoring. CONCLUSIONS: This consensus provides 44 statements that can be used at the bedside to diagnose, treat and monitor patients with shock

Asteroseismology and Interferometry

Asteroseismology provides us with a unique opportunity to improve our understanding of stellar structure and evolution. Recent developments, including the first systematic studies of solar-like pulsators, have boosted the impact of this field of research within Astrophysics and have led to a significant increase in the size of the research community. In the present paper we start by reviewing the basic observational and theoretical properties of classical and solar-like pulsators and present results from some of the most recent and outstanding studies of these stars. We centre our review on those classes of pulsators for which interferometric studies are expected to provide a significant input. We discuss current limitations to asteroseismic studies, including difficulties in mode identification and in the accurate determination of global parameters of pulsating stars, and, after a brief review of those aspects of interferometry that are most relevant in this context, anticipate how interferometric observations may contribute to overcome these limitations. Moreover, we present results of recent pilot studies of pulsating stars involving both asteroseismic and interferometric constraints and look into the future, summarizing ongoing efforts concerning the development of future instruments and satellite missions which are expected to have an impact in this field of research.Comment: Version as published in The Astronomy and Astrophysics Review, Volume 14, Issue 3-4, pp. 217-36

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Resolving the neural circuits of anxiety

Although anxiety disorders represent a major societal problem demanding new therapeutic targets, these efforts have languished in the absence of a mechanistic understanding of this subjective emotional state. While it is impossible to know with certainty the subjective experience of a rodent, rodent models hold promise in dissecting well-conserved limbic circuits. The application of modern approaches in neuroscience has already begun to unmask the neural circuit intricacies underlying anxiety by allowing direct examination of hypotheses drawn from existing psychological concepts. This information points toward an updated conceptual model for what neural circuit perturbations could give rise to pathological anxiety and thereby provides a roadmap for future therapeutic development.National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (NIH Director’s New Innovator Award DP2-DK-102256-01)National Institute of Mental Health (U.S.) (NIH) R01-MH102441-01)JPB Foundatio

Increasing vegetable intakes: rationale and systematic review of published interventions

Purpose While the health benefits of a high fruit and vegetable consumption are well known and considerable work has attempted to improve intakes, increasing evidence also recognises a distinction between fruit and vegetables, both in their impacts on health and in consumption patterns. Increasing work suggests health benefits from a high consumption specifically of vegetables, yet intakes remain low, and barriers to increasing intakes are prevalent making intervention difficult. A systematic review was undertaken to identify from the published literature all studies reporting an intervention to increase intakes of vegetables as a distinct food group. Methods Databases—PubMed, PsychInfo and Medline—were searched over all years of records until April 2015 using pre-specified terms. Results Our searches identified 77 studies, detailing 140 interventions, of which 133 (81 %) interventions were conducted in children. Interventions aimed to use or change hedonic factors, such as taste, liking and familiarity (n = 72), use or change environmental factors (n = 39), use or change cognitive factors (n = 19), or a combination of strategies (n = 10). Increased vegetable acceptance, selection and/or consumption were reported to some degree in 116 (83 %) interventions, but the majority of effects seem small and inconsistent. Conclusions Greater percent success is currently found from environmental, educational and multi-component interventions, but publication bias is likely, and long-term effects and cost-effectiveness are rarely considered. A focus on long-term benefits and sustained behaviour change is required. Certain population groups are also noticeably absent from the current list of tried interventions

Cross-Species Affective Neuroscience Decoding of the Primal Affective Experiences of Humans and Related Animals

BACKGROUND: The issue of whether other animals have internally felt experiences has vexed animal behavioral science since its inception. Although most investigators remain agnostic on such contentious issues, there is now abundant experimental evidence indicating that all mammals have negatively and positively-valenced emotional networks concentrated in homologous brain regions that mediate affective experiences when animals are emotionally aroused. That is what the neuroscientific evidence indicates. PRINCIPAL FINDINGS: The relevant lines of evidence are as follows: 1) It is easy to elicit powerful unconditioned emotional responses using localized electrical stimulation of the brain (ESB); these effects are concentrated in ancient subcortical brain regions. Seven types of emotional arousals have been described; using a special capitalized nomenclature for such primary process emotional systems, they are SEEKING, RAGE, FEAR, LUST, CARE, PANIC/GRIEF and PLAY. 2) These brain circuits are situated in homologous subcortical brain regions in all vertebrates tested. Thus, if one activates FEAR arousal circuits in rats, cats or primates, all exhibit similar fear responses. 3) All primary-process emotional-instinctual urges, even ones as complex as social PLAY, remain intact after radical neo-decortication early in life; thus, the neocortex is not essential for the generation of primary-process emotionality. 4) Using diverse measures, one can demonstrate that animals like and dislike ESB of brain regions that evoke unconditioned instinctual emotional behaviors: Such ESBs can serve as 'rewards' and 'punishments' in diverse approach and escape/avoidance learning tasks. 5) Comparable ESB of human brains yield comparable affective experiences. Thus, robust evidence indicates that raw primary-process (i.e., instinctual, unconditioned) emotional behaviors and feelings emanate from homologous brain functions in all mammals (see Appendix S1), which are regulated by higher brain regions. Such findings suggest nested-hierarchies of BrainMind affective processing, with primal emotional functions being foundational for secondary-process learning and memory mechanisms, which interface with tertiary-process cognitive-thoughtful functions of the BrainMind

Response Properties of Human Amygdala Subregions: Evidence Based on Functional MRI Combined with Probabilistic Anatomical Maps

The human amygdala is thought to play a pivotal role in the processing of emotionally significant sensory information. The major subdivisions of the human amygdala—the laterobasal group (LB), the superficial group (SF), and the centromedial group (CM)—have been anatomically delineated, but the functional response properties of these amygdala subregions in humans are still unclear. We combined functional MRI with cyto-architectonically defined probabilistic maps to analyze the response characteristics of amygdala subregions in subjects presented with auditory stimuli. We found positive auditory stimulation-related signal changes predominantly in probabilistically defined LB, and negative responses predominantly in SF and CM. In the left amygdala, mean response magnitude in the core area of LB with 90–100% assignment probability was significantly larger than in the core areas of SF and CM. These differences were observed for pleasant and unpleasant stimuli. Our findings reveal that the probabilistically defined anatomical subregions of the human amygdala show distinctive fMRI response patterns. The stronger auditory responses in LB as compared with SF and CM may reflect a predominance of auditory inputs to human LB, similar to many animal species in which the majority of sensory, including auditory, afferents project to this subdivision of the amygdala. Our study indicates that the intrinsic functional differentiation of the human amygdala may be probed using fMRI combined with probabilistic anatomical maps

The relationship between various measures of obesity and arterial stiffness in morbidly obese patients

<p>Abstract</p> <p>Background</p> <p>Obesity is associated with increased risk of cardiovascular disease. Arterial stiffness assessed by carotid femoral pulse wave velocity (PWV) is an independent predictor of cardiovascular morbidity and mortality. We aimed to investigate how various measures of body composition affect arterial stiffness.</p> <p>Methods</p> <p>This is an analysis of cross-sectional baseline data from a controlled clinical trial addressing changes in arterial stiffness after either surgery or lifestyle intervention in a population of morbidly obese patients. High-fidelity applanation tonometry (Millar^®, Sphygmocor^®) was used to measure pulse wave velocity (PWV). Carotid femoral PWV is a direct measure of arterial stiffness and is considered to be the gold standard method. The Inbody 720 Body Composition Analyzer was used for bioelectrical impedance analysis (BIA). Spearman's correlation, independent samples <it>t</it>-test, chi-square tests, Fisher's exact test and multiple linear regression analyses were used as statistical methods.</p> <p>Results</p> <p>A total of 133 patients (79 women), with a mean (SD) age of 43 (11) years were included in the study. Men had a significantly higher prevalence of obesity related comorbidities and significantly higher PWV, 9.1 (2.0) m/s vs. 8.1 (1.8) m/s, p = 0.003, than women. In the female group, PWV was positively correlated with WC, WHtR, BMI and visceral fat area. In the male group, PWV was negatively correlated with BMI. Multiple linear regression analysis showed that increasing BMI, WC, WHtR, visceral fat area and fat mass were independently associated with higher PWV in women, but not in men, after adjustment for age, hypertension and type 2 diabetes.</p> <p>Conclusion</p> <p>Most measures of general and abdominal obesity were predictors of arterial stiffness in female morbidly obese patients.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Identifier <a href="http://www.clinicaltrials.gov/ct2/show/NCT00626964">NCT00626964</a></p