Role of N-methyl-D-aspartate receptors in action-based predictive coding deficits in schizophrenia

Published in final edited form as:Biol Psychiatry. 2017 March 15; 81(6): 514–524. doi:10.1016/j.biopsych.2016.06.019.BACKGROUND: Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia. METHODS: In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback (listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event-related potentials during the talk/listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case-control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared. RESULTS: N1 suppression to self-produced vocalizations was significantly and similarly diminished by ketamine (Cohen’s d = 1.14) and schizophrenia (Cohen’s d = .85). CONCLUSIONS: Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia.This work was supported by AstraZeneca for an investigator-initiated study (DHM) and the National Institute of Mental Health Grant Nos. R01 MH-58262 (to JMF) and T32 MH089920 (to NSK). JHK was supported by the Yale Center for Clinical Investigation Grant No. UL1RR024139 and the US National Institute on Alcohol Abuse and Alcoholism Grant No. P50AA012879. (AstraZeneca for an investigator-initiated study (DHM); R01 MH-58262 - National Institute of Mental Health; T32 MH089920 - National Institute of Mental Health; UL1RR024139 - Yale Center for Clinical Investigation; P50AA012879 - US National Institute on Alcohol Abuse and Alcoholism)Accepted manuscrip

Patterns and outcomes of preterm hospital admissions during pregnancy in NSW, 2001-2008

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Electron transport and energy relaxation in dilute magnetic alloys

We consider the effect of the RKKY interaction between magnetic impurities on the electron relaxation rates in a normal metal. The interplay between the RKKY interaction and the Kondo effect may result in a non-monotonic temperature dependence of the electron momentum relaxation rate, which determines the Drude conductivity. The electron phase relaxation rate, which determines the magnitude of the weak localization correction to the resistivity, is also a non-monotonic function of temperature. For this function, we find the dependence of the position of its maximum on the concentration of magnetic impurities. We also relate the electron energy relaxation rate to the excitation spectrum of the system of magnetic impurities. The energy relaxation determines the distribution function for the out-of-equilibrium electrons. Measurement of the electron distribution function thus may provide information about the excitations in the spin glass phase.Comment: 15 pages, 5 figure

Effect of exacerbation history on clinical response to dupilumab in moderate-to-severe uncontrolled asthma

Background The phase 3 LIBERTY ASTHMA QUEST study (ClinicalTrials.gov: NCT02414854) in patients with uncontrolled, moderate-to-severe asthma has demonstrated the efficacy and safety of dupilumab 200 and 300 mg every 2 weeks versus placebo. This post hoc analysis assessed the effect of dupilumab on efficacy outcomes and asthma control across a range of historical exacerbation rates in patients with type 2-high asthma. Methods Annualised severe exacerbation rates over the 52-week treatment period, pre-bronchodilator forced expiratory volume in 1 s (FEV1) at weeks 12 and 52, and the five-item Asthma Control Questionnaire (ACQ-5) score at weeks 24 and 52 were assessed in patients with ≥1, ≥2 or ≥3 exacerbations in the previous year. Subgroups were stratified by baseline blood eosinophils ≥150 or ≥300 cells·μL-1 or baseline exhaled nitric oxide fraction ≥25 ppb and baseline inhaled corticosteroid (ICS) dose. Results Across all type 2-high subgroups, dupilumab versus placebo significantly reduced severe exacerbations by 54–90%, with greater improvements in patients with more exacerbations prior to study initiation. Similarly, improvements in FEV1 (least squares (LS) mean difference versus placebo: ≥1 exacerbations, 0.15–0.25 L; ≥2 exacerbations, 0.12–0.32 L; ≥3 exacerbations, 0.09–0.38 L; majority p<0.05) and ACQ-5 score (LS mean difference range: ≥1 exacerbations, -0.30 to -0.57; ≥2 exacerbations, -0.29 to -0.56; ≥3 exacerbations, -0.43 to -0.61; all p<0.05) were observed, irrespective of prior exacerbation history, across all subgroups. Conclusions Dupilumab significantly reduced severe exacerbations and improved FEV1 and asthma control in patients with elevated type 2 biomarkers irrespective of exacerbation history and baseline ICS dose

Pulse-Shape discrimination with the Counting Test Facility

Pulse shape discrimination (PSD) is one of the most distinctive features of liquid scintillators. Since the introduction of the scintillation techniques in the field of particle detection, many studies have been carried out to characterize intrinsic properties of the most common liquid scintillator mixtures in this respect. Several application methods and algorithms able to achieve optimum discrimination performances have been developed. However, the vast majority of these studies have been performed on samples of small dimensions. The Counting Test Facility, prototype of the solar neutrino experiment Borexino, as a 4 ton spherical scintillation detector immersed in 1000 tons of shielding water, represents a unique opportunity to extend the small-sample PSD studies to a large-volume setup. Specifically, in this work we consider two different liquid scintillation mixtures employed in CTF, illustrating for both the PSD characterization results obtained either with the processing of the scintillation waveform through the optimum Gatti's method, or via a more conventional approach based on the charge content of the scintillation tail. The outcomes of this study, while interesting per se, are also of paramount importance in view of the expected Borexino detector performances, where PSD will be an essential tool in the framework of the background rejection strategy needed to achieve the required sensitivity to the solar neutrino signals.Comment: 39 pages, 17 figures, submitted to Nucl. Instr. Meth.

Measurement of the scintillation time spectra and pulse-shape discrimination of low-energy beta and nuclear recoils in liquid argon with DEAP-1

The DEAP-1 low-background liquid argon detector was used to measure scintillation pulse shapes of electron and nuclear recoil events and to demonstrate the feasibility of pulse-shape discrimination (PSD) down to an electron-equivalent energy of 20 keV. In the surface dataset using a triple-coincidence tag we found the fraction of beta events that are misidentified as nuclear recoils to be $<1.4\times 10^{-7}$ (90% C.L.) for energies between 43-86 keVee and for a nuclear recoil acceptance of at least 90%, with 4% systematic uncertainty on the absolute energy scale. The discrimination measurement on surface was limited by nuclear recoils induced by cosmic-ray generated neutrons. This was improved by moving the detector to the SNOLAB underground laboratory, where the reduced background rate allowed the same measurement with only a double-coincidence tag. The combined data set contains $1.23\times10^8$ events. One of those, in the underground data set, is in the nuclear-recoil region of interest. Taking into account the expected background of 0.48 events coming from random pileup, the resulting upper limit on the electronic recoil contamination is $<2.7\times10^{-8}$ (90% C.L.) between 44-89 keVee and for a nuclear recoil acceptance of at least 90%, with 6% systematic uncertainty on the absolute energy scale. We developed a general mathematical framework to describe PSD parameter distributions and used it to build an analytical model of the distributions observed in DEAP-1. Using this model, we project a misidentification fraction of approx. $10^{-10}$ for an electron-equivalent energy threshold of 15 keV for a detector with 8 PE/keVee light yield. This reduction enables a search for spin-independent scattering of WIMPs from 1000 kg of liquid argon with a WIMP-nucleon cross-section sensitivity of $10^{-46}$ cm$^2$, assuming negligible contribution from nuclear recoil backgrounds.Comment: Accepted for publication in Astroparticle Physic

A Measurement of the Branching Ratio of KL→e+e−γγK_L \to e^+e^-\gamma\gamma

We report on a study of the decay $K_L \to e^+e^-\gamma\gamma$ carried out as a part of the KTeV/E799 experiment at Fermilab. The 1997 data yielded a sample of 1543 events, including an expected background of $56 \pm 8$ events. An effective form factor was determined from the observed distribution of the $e^+e^-$ invariant mass. Using this form factor in the calculation of the detector acceptance, the branching ratio was measured to be ${\mathcal B}(K_L \to e^+ e^- \gamma \gamma, E^*_\gamma > 5 {MeV}) = (5.84 \pm 0.15 {\rm ~(stat)} \pm 0.32 {\rm ~(sys)})\times 10^{-7}$.Comment: 5 pages, 4 figure