The central limit problem for random vectors with symmetries

Motivated by the central limit problem for convex bodies, we study normal approximation of linear functionals of high-dimensional random vectors with various types of symmetries. In particular, we obtain results for distributions which are coordinatewise symmetric, uniform in a regular simplex, or spherically symmetric. Our proofs are based on Stein's method of exchangeable pairs; as far as we know, this approach has not previously been used in convex geometry and we give a brief introduction to the classical method. The spherically symmetric case is treated by a variation of Stein's method which is adapted for continuous symmetries.Comment: AMS-LaTeX, uses xy-pic, 23 pages; v3: added new corollary to Theorem

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

Background: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Findings: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88–1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90–1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41–0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22–3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31–0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64–0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37–3·91], p=0·771) was similar. Interpretation: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status

Prehospital 12-Lead Electrocardiogram within 60 Minutes Differentiates Proximal versus Nonproximal Left Anterior Descending Artery Myocardial Infarction

<p>Introduction: Acute anterior myocardial infarctions caused by proximal left anterior descending (LAD) artery occlusions are associated with a higher morbidity and mortality. Early identification of high-risk patients via the 12-lead electrocardiogram (ECG) could assist physicians and emergency response teams in providing early and aggressive care for patients with anterior ST-elevation myocardial infarctions (STEMI). Approximately 25% of US hospitals have primary percutaneous coronary intervention (PCI) capability for the treatment of acute myocardial infarctions. Given the paucity of</p> <p>hospitals capable of PCI, early identification of more severe myocardial infarction may prompt</p> <p>emergency medical service routing of these patients to PCI-capable hospitals. We sought to determine if the 12 lead ECG is capable of predicting proximal LAD artery occlusions.</p> <p>Methods: In a retrospective, post-hoc analysis of the Pre-Hospital Administration of Thrombolytic Therapy with Urgent Culprit Artery Revascularization pilot trial, we compared the ECG findings of</p> <p>proximal and nonproximal LAD occlusions for patients who had undergone an ECG within 180 minutes of symptom onset.</p> <p>Results: In this study, 72 patients had anterior STEMIs, with ECGs performed within 180 minutes of symptom onset. In patients who had undergone ECGs within 60 minutes (n¼35), the mean sum of ST elevation (STE) in leads V1 through V6 plus ST depression (STD) in leads II, III, and aVF was 19.2 mm for proximal LAD occlusions and 11.7 mm for nonproximal LAD occlusions (P¼0.007). A sum STE in V1 through V6 plus STD in II, III, and aVF of at least 17.5 mm had a sensitivity of 52.3%, specificity of 92.9%, positive predictive value of 91.7%, and negative predictive value of 56.5% for proximal LAD occlusions. When the ECG was performed more than 60 minutes after symptom onset (n¼37), there was no significant difference in ST-segment deviation between the 2 groups.</p> <p>Conclusion: The sum STE (V1-V6) and STD (II, III, aVF) on a 12-lead ECG can be used to predict proximal LAD occlusions if performed within the first hour of symptom onset. This should be considered a high-risk finding and may prompt prehospital direction of such patients to PCI-capable hospitals. [West J Emerg Med. 2011;12(4):408–413.]</p

Effects of affective picture viewing on postural control

<p>Abstract</p> <p>Background</p> <p>Emotion theory holds that unpleasant events prime withdrawal actions, whereas pleasant events prime approach actions. Recent studies have suggested that passive viewing of emotion eliciting images results in postural adjustments, which become manifest as changes in body center of pressure (COP) trajectories. From those studies it appears that posture is modulated most when viewing pictures with negative valence. The present experiment was conducted to test the hypothesis that pictures with negative valence have a greater impact on postural control than neutral or positive ones. Thirty-four healthy subjects passively viewed a series of emotion eliciting images, while standing either in a bipedal or unipedal stance on a force plate. The images were adopted from the International Affective Picture System (IAPS). We analysed mean and variability of the COP and the length of the associated sway path as a function of emotion.</p> <p>Results</p> <p>The mean position of the COP was unaffected by emotion, but unipedal stance resulted in overall greater body sway than bipedal stance. We found a modest effect of emotion on COP: viewing pictures of mutilation resulted in a smaller sway path, but only in unipedal stance. We obtained valence and arousal ratings of the images with an independent sample of viewers. These subjects rated the unpleasant images as significantly less pleasant than neutral images, and the pleasant images as significantly more pleasant than neutral images. However, the subjects rated the images as overall less pleasant and less arousing than viewers in a closely comparable American study, pointing to unknown differences in viewer characteristics.</p> <p>Conclusion</p> <p>Overall, viewing emotion eliciting images had little effect on body sway. Our finding of a reduction in sway path length when viewing pictures of mutilation was indicative of a freezing strategy, i.e. fear bradycardia. The results are consistent with current knowledge about the neuroanatomical organization of the emotion system and the neural control of behavior.</p

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

Electrophysiological Characterization of The Cerebellum in the Arterially Perfused Hindbrain and Upper Body of The Rat

In the present study, a non-pulsatile arterially perfused hindbrain and upper body rat preparation is described which is an extension of the brainstem preparation reported by Potts et al., (Brain Res Bull 53(1):59–67), 1. The modified in situ preparation allows study of cerebellar function whilst preserving the integrity of many of its interconnections with the brainstem, upper spinal cord and the peripheral nervous system of the head and forelimbs. Evoked mossy fibre, climbing fibre and parallel fibre field potentials and EMG activity elicited in forelimb biceps muscle by interpositus stimulation provided evidence that both cerebellar inputs and outputs remain operational in this preparation. Similarly, the spontaneous and evoked single unit activity of Purkinje cells, putative Golgi cells, molecular interneurones and cerebellar nuclear neurones was similar to activity patterns reported in vivo. The advantages of the preparation include the ability to record, without the complications of anaesthesia, stabile single unit activity for extended periods (3 h or more), from regions of the rat cerebellum that are difficult to access in vivo. The preparation should therefore be a useful adjunct to in vitro and in vivo studies of neural circuits underlying cerebellar contributions to movement control and motor learning

Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition

Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modelling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4BY358C mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioural assays, PDE4BY358C mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4BY358C mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 hours, was decreased at 7 days in PDE4BY358C mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signalling by PDE4B in a very late phase of consolidation. No effect of the PDE4BY358C mutation was observed in the pre-pulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory

A multimeasure approach to investigating affective appraisal of social information in Williams syndrome

People with Williams syndrome (WS) have been consistently described as showing heightened sociability, gregariousness, and interest in people, in conjunction with an uneven cognitive profile and mild to moderate intellectual or learning disability. To explore the mechanisms underlying this unusual social–behavioral phenotype, we investigated whether individuals with WS show an atypical appraisal style and autonomic responsiveness to emotionally laden images with social or nonsocial content. Adolescents and adults with WS were compared to chronological age-matched and nonverbal mental age-matched groups in their responses to positive and negative images with or without social content, using measures of self-selected viewing time (SSVT), autonomic arousal reflected in pupil dilation measures, and likeability ratings. The participants with WS looked significantly longer at the social images compared to images without social content and had reduced arousal to the negative social images compared to the control groups. In contrast to the comparison groups, the explicit ratings of likeability in the WS group did not correlate with their SSVT; instead, they reflected an appraisal style of more extreme ratings. This distinctive pattern of viewing interest, likeability ratings, and autonomic arousal to images with social content in the WS group suggests that their heightened social drive may be related to atypical functioning of reward-related brain systems reflected in SSVT and autonomic reactivity measures, but not in explicit ratings

Early predictors of impaired social functioning in male rhesus macaques (Macaca mulatta)

Autism spectrum disorder (ASD) is characterized by social cognition impairments but its basic disease mechanisms remain poorly understood. Progress has been impeded by the absence of animal models that manifest behavioral phenotypes relevant to ASD. Rhesus monkeys are an ideal model organism to address this barrier to progress. Like humans, rhesus monkeys are highly social, possess complex social cognition abilities, and exhibit pronounced individual differences in social functioning. Moreover, we have previously shown that Low-Social (LS) vs. High-Social (HS) adult male monkeys exhibit lower social motivation and poorer social skills. It is not known, however, when these social deficits first emerge. The goals of this study were to test whether juvenile LS and HS monkeys differed as infants in their ability to process social information, and whether infant social abilities predicted later social classification (i.e., LS vs. HS), in order to facilitate earlier identification of monkeys at risk for poor social outcomes. Social classification was determined for N = 25 LS and N = 25 HS male monkeys that were 1–4 years of age. As part of a colony-wide assessment, these monkeys had previously undergone, as infants, tests of face recognition memory and the ability to respond appropriately to conspecific social signals. Monkeys later identified as LS vs. HS showed impairments in recognizing familiar vs. novel faces and in the species-typical adaptive ability to gaze avert to scenes of conspecific aggression. Additionally, multivariate logistic regression using infant social ability measures perfectly predicted later social classification of all N = 50 monkeys. These findings suggest that an early capacity to process important social information may account for differences in rhesus monkeys’ motivation and competence to establish and maintain social relationships later in life. Further development of this model will facilitate identification of novel biological targets for intervention to improve social outcomes in at-risk young monkeys