Shift toward prior knowledge confers a perceptual advantage in early psychosis and psychosis-prone healthy individuals.

Many neuropsychiatric illnesses are associated with psychosis, i.e., hallucinations (perceptions in the absence of causative stimuli) and delusions (irrational, often bizarre beliefs). Current models of brain function view perception as a combination of two distinct sources of information: bottom-up sensory input and top-down influences from prior knowledge. This framework may explain hallucinations and delusions. Here, we characterized the balance between visual bottom-up and top-down processing in people with early psychosis (study 1) and in psychosis-prone, healthy individuals (study 2) to elucidate the mechanisms that might contribute to the emergence of psychotic experiences. Through a specialized mental-health service, we identified unmedicated individuals who experience early psychotic symptoms but fall below the threshold for a categorical diagnosis. We observed that, in early psychosis, there was a shift in information processing favoring prior knowledge over incoming sensory evidence. In the complementary study, we capitalized on subtle variations in perception and belief in the general population that exhibit graded similarity with psychotic experiences (schizotypy). We observed that the degree of psychosis proneness in healthy individuals, and, specifically, the presence of subtle perceptual alterations, is also associated with stronger reliance on prior knowledge. Although, in the current experimental studies, this shift conferred a performance benefit, under most natural viewing situations, it may provoke anomalous perceptual experiences. Overall, we show that early psychosis and psychosis proneness both entail a basic shift in visual information processing, favoring prior knowledge over incoming sensory evidence. The studies provide complementary insights to a mechanism by which psychotic symptoms may emerge.

Modelling the impact of lockdown-easing measures on cumulative COVID-19 cases and deaths in England.

OBJECTIVES: To assess the potential impacts of successive lockdown-easing measures in England, at a point in the COVID-19 pandemic when community transmission levels were relatively high. DESIGN: We developed a Bayesian model to infer incident cases and reproduction number (R) in England, from incident death data. We then used this to forecast excess cases and deaths in multiple plausible scenarios in which R increases at one or more time points. SETTING: England. PARTICIPANTS: Publicly available national incident death data for COVID-19 were examined. PRIMARY OUTCOME: Excess cumulative cases and deaths forecast at 90 days, in simulated scenarios of plausible increases in R after successive easing of lockdown in England, compared with a baseline scenario where R remained constant. RESULTS: Our model inferred an R of 0.75 on 13 May when England first started easing lockdown. In the most conservative scenario modelled where R increased to 0.80 as lockdown was eased further on 1 June and then remained constant, the model predicted an excess 257 (95% CI 108 to 492) deaths and 26 447 (95% CI 11 105 to 50 549) cumulative cases over 90 days. In the scenario with maximal increases in R (but staying ≤1), the model predicts 3174 (95% CI 1334 to 6060) excess cumulative deaths and 421 310 (95% CI 177 012 to 804 811) cases. Observed data from the forecasting period aligned most closely to the scenario in which R increased to 0.85 on 1 June, and 0.9 on 4 July. CONCLUSIONS: When levels of transmission are high, even small changes in R with easing of lockdown can have significant impacts on expected cases and deaths, even if R remains ≤1. This will have a major impact on population health, tracing systems and healthcare services in England. Following an elimination strategy rather than one of maintenance of R ≤1 would substantially mitigate the impact of the COVID-19 epidemic within England.

Disaggregating physiological components of cortisol output: A novel approach to cortisol analysis in a clinical sample - A proof-of-principle study.

Although childhood adversity (CA) increases risk for subsequent mental illnesses, developmental mechanisms underpinning this association remain unclear. The hypothalamic-pituitary-adrenal axis (HPAA) is one candidate system potentially linking CA with psychopathology. However, determining developmental effects of CA on HPAA output and differentiating these from effects of current illness has proven difficult. Different aspects of HPAA output are governed by differentiable physiological mechanisms. Disaggregating HPAA output according to its biological components (baseline tonic cortisol, background diurnal variation, phasic stress response) may improve precision of associations with CA and/or psychopathology. In a novel proof-of-principle investigation we test whether different predictors, CA (distal risk factor) and current depressive symptoms, show distinct associations with dissociable HPAA components. A clinical group (aged 16-25) at high-risk for developing severe psychopathology (n = 20) were compared to age and sex matched healthy controls (n = 21). Cortisol was measured at waking (x4), following stress induction (x8), and during a time-environment-matched non-stress condition. Using piecewise multilevel modeling, stress responses were disaggregated into increase and decrease, while controlling for waking cortisol, background diurnal output and confounding variables. Elevated waking cortisol was specifically associated with higher CA scores. Higher non-stress cortisol was specifically associated with higher depressive scores. Following stress induction, depressive symptoms attenuated cortisol increase, whilst CA attenuated cortisol decrease. The results support a differential HPAA dysregulation hypothesis where physiologically dissociable components of HPAA output are differentially associated with distal (CA) or proximal (depressive symptoms) predictors. This proof-of-principle study demonstrates that future cortisol analyses need to disaggregate biologically independent mechanisms of HPAA output.

Opioid Antagonists and the A118G Polymorphism in the µ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype.

This corrects the article DOI: 10.1038/npp.2016.60.

Opioid Antagonists and the A118G Polymorphism in the µ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype.

The A118G single-nucleotide polymorphism (SNP rs1799971) in the µ-opioid receptor gene, OPRM1, has been much studied in relation to alcohol use disorders. The reported effects of allelic variation at this SNP on alcohol-related behaviors, and on opioid receptor antagonist treatments, have been inconsistent. We investigated the pharmacogenetic interaction between A118G variation and the effects of two µ-opioid receptor antagonists in a clinical lab setting. Fifty-six overweight and moderate-heavy drinkers were prospectively stratified by genotype (29 AA homozygotes, 27 carriers of at least 1 G allele) in a double-blind placebo-controlled, three-period crossover design with naltrexone (NTX; 25 mg OD for 2 days, then 50 mg OD for 3 days) and GSK1521498 (10 mg OD for 5 days). The primary end point was regional brain activation by the contrast between alcohol and neutral tastes measured using functional magnetic resonance imaging (fMRI). Secondary end points included other fMRI contrasts, subjective responses to intravenous alcohol challenge, and food intake. GSK1521498 (but not NTX) significantly attenuated fMRI activation by appetitive tastes in the midbrain and amygdala. GSK1521498 (and NTX to a lesser extent) significantly affected self-reported responses to alcohol infusion. Both drugs reduced food intake. Across all end points, there was less robust evidence for significant effects of OPRM1 allelic variation, or for pharmacogenetic interactions between genotype and drug treatment. These results do not support strong modulatory effects of OPRM1 genetic variation on opioid receptor antagonist attenuation of alcohol- and food-related behaviors. However, they do support further investigation of GSK1521498 as a potential therapeutic for alcohol use and eating disorders.

Development of a broadband picosecond infrared spectrometer and its incorporation into an existing ultrafast time-resolved resonance Raman, UV/visible, and fluorescence spectroscopic apparatus.

We have constructed a broadband ultrafast time-resolved infrared (TRIR) spectrometer and incorporated it into our existing time-resolved spectroscopy apparatus, thus creating a single instrument capable of performing the complementary techniques of femto-/picosecond time-resolved resonance Raman (TR3), fluorescence, and UV/visible/infrared transient absorption spectroscopy. The TRIR spectrometer employs broadband (150 fs, approximately 150 cm(-1) FWHM) mid-infrared probe and reference pulses (generated by difference frequency mixing of near-infrared pulses in type I AgGaS2), which are dispersed over two 64-element linear infrared array detectors (HgCdTe). These are coupled via custom-built data acquisition electronics to a personal computer for data processing. This data acquisition system performs signal handling on a shot-by-shot basis at the 1 kHz repetition rate of the pulsed laser system. The combination of real-time signal processing and the ability to normalize each probe and reference pulse has enabled us to achieve a high sensitivity on the order of deltaOD approximately 10(-4) - 10(-5) with 1 min of acquisition time. We present preliminary picosecond TRIR studies using this spectrometer and also demonstrate how a combination of TRIR and TR3 spectroscopy can provide key information for the full elucidation of a photochemical process.

Studying food reward and motivation in humans.

A key challenge in studying reward processing in humans is to go beyond subjective self-report measures and quantify different aspects of reward such as hedonics, motivation, and goal value in more objective ways. This is particularly relevant for the understanding of overeating and obesity as well as their potential treatments. In this paper are described a set of measures of food-related motivation using handgrip force as a motivational measure. These methods can be used to examine changes in food related motivation with metabolic (satiety) and pharmacological manipulations and can be used to evaluate interventions targeted at overeating and obesity. However to understand food-related decision making in the complex food environment it is essential to be able to ascertain the reward goal values that guide the decisions and behavioral choices that people make. These values are hidden but it is possible to ascertain them more objectively using metrics such as the willingness to pay and a method for this is described. Both these sets of methods provide quantitative measures of motivation and goal value that can be compared within and between individuals.

Attribution of intentional causation influences the perception of observed movements: behavioral evidence and neural correlates.

Recent research on human agency suggests that intentional causation is associated with a subjective compression in the temporal interval between actions and their effects. That is, intentional movements and their causal effects are perceived as closer together in time than equivalent unintentional movements and their causal effects. This so-called intentional binding effect is consistently found for one's own self-generated actions. It has also been suggested that intentional binding occurs when observing intentional movements of others. However, this evidence is undermined by limitations of the paradigm used. In the current study we aimed to overcome these limitations using a more rigorous design in combination with functional Magnetic Resonance Imaging (fMRI) to explore the neural underpinnings of intentional binding of observed movements. In particular, we aimed to identify brain areas sensitive to the interaction between intentionality and causality attributed to the observed action. Our behavioral results confirmed the occurrence of intentional binding for observed movements using this more rigorous paradigm. Our fMRI results highlighted a collection of brain regions whose activity was sensitive to the interaction between intentionality and causation. Intriguingly, these brain regions have previously been implicated in the sense of agency over one's own movements. We discuss the implications of these results for intentional binding specifically, and the sense of agency more generally.

Neural and behavioral effects of a novel mu opioid receptor antagonist in binge-eating obese people.

BACKGROUND: Binge eating is associated with obesity and has been conceptualized as "food addiction." However, this view has received only inconsistent support in humans, and limited evidence relates key neurocircuitry to the disorder. Moreover, relatively few studies have used pharmacologic functional magnetic resonance imaging to probe the underlying basis of altered eating behaviors. METHODS: In a double-blind, placebo-controlled, parallel group study, we explored the effects of a potent mu-opioid receptor antagonist, GSK1521498, in obese individuals with moderate binge eating. Subjects were tested during a baseline placebo run-in period and retested after 28-days of drug (n = 21) or placebo (n = 21) treatment. Using functional magnetic resonance imaging and behavioral measures, we determined the drug's effects on brain responses to food images and, separately, on motivation to expend energy to view comparable images. RESULTS: Compared with placebo, GSK1521498 was associated with a significant reduction in pallidum/putamen responses to pictures of high-calorie food and a reduction in motivation to view images of high-calorie food. Intriguingly, although motivational responding was reduced, subjective liking for the same images actually increased following drug treatment. CONCLUSIONS: Stimulus-specific putamen/pallidal responses in obese people with binge eating are sensitive to altered mu-opioid function. This neuromodulation was accompanied by reductions in motivational responding, as measured by grip force, although subjective liking responses to the same stimuli actually increased. As well as providing evidence for a link between the opioid system and food-related behavior in binge-eating obese individuals, these results support a dissociation across measures of motivation and liking associated with food-related stimuli in these individuals.

CamBAfx: Workflow Design, Implementation and Application for Neuroimaging.

CamBAfx is a workflow application designed for both researchers who use workflows to process data (consumers) and those who design them (designers). It provides a front-end (user interface) optimized for data processing designed in a way familiar to consumers. The back-end uses a pipeline model to represent workflows since this is a common and useful metaphor used by designers and is easy to manipulate compared to other representations like programming scripts. As an Eclipse Rich Client Platform application, CamBAfx's pipelines and functions can be bundled with the software or downloaded post-installation. The user interface contains all the workflow facilities expected by consumers. Using the Eclipse Extension Mechanism designers are encouraged to customize CamBAfx for their own pipelines. CamBAfx wraps a workflow facility around neuroinformatics software without modification. CamBAfx's design, licensing and Eclipse Branding Mechanism allow it to be used as the user interface for other software, facilitating exchange of innovative computational tools between originating labs.