Reflection impulsivity in binge drinking: behavioural and volumetric correlates.

The degree to which an individual accumulates evidence prior to making a decision, also known as reflection impulsivity, can be affected in psychiatric disorders. Here, we study decisional impulsivity in binge drinkers, a group at elevated risk for developing alcohol use disorders, comparing two tasks assessing reflection impulsivity and a delay discounting task, hypothesizing impairments in both subtypes of impulsivity. We also assess volumetric correlates of reflection impulsivity focusing on regions previously implicated in functional magnetic resonance imaging studies. Sixty binge drinkers and healthy volunteers were tested using two different information-gathering paradigms: the beads task and the Information Sampling Task (IST). The beads task was analysed using a behavioural approach and a Bayesian model of decision making. Delay discounting was assessed using the Monetary Choice Questionnaire. Regression analyses of primary outcomes were conducted with voxel-based morphometry analyses. Binge drinkers sought less evidence prior to decision in the beads task compared with healthy volunteers in both the behavioural and computational modelling analysis. There were no group differences in the IST or delay discounting task. Greater impulsivity as indexed by lower evidence accumulation in the beads task was associated with smaller dorsolateral prefrontal cortex and inferior parietal volumes. In contrast, greater impulsivity as indexed by lower evidence accumulation in the IST was associated with greater dorsal cingulate and precuneus volumes. Binge drinking is characterized by impaired reflection impulsivity suggesting a deficit in deciding on the basis of future outcomes that are more difficult to represent. These findings emphasize the role of possible therapeutic interventions targeting decision-making deficits.The study was supported by theWellcome Trust grant to VV (093705/10/Z) and to NA Harrison. PB is supported by the Portuguese Foundation for Science and Technology (individual fellowship to PB: SFRH/BD/33889/ 2009). YW is supported by the Fyssen Fondation. MM is supported by the Welcome Trust and the Biomedical Research Centre.Wewould also like to thank theWolfson Brain Imaging Center staff for their expertise with collecting the imaging data and all the participants for their involvement in this study. The Behavioural and Clinical Neuroscience Institute is supported by the Wellcome Trust and Medical Research Council.This is the final published version. It first appeared from Wiley via http://dx.doi.org/10.1111/adb.1222

A new ceramide along with eight known compounds from the roots of Artemisia incisa pamp

A new compound (1) (named as artemceramide-B) together with eight known compounds (taraxerol (2), taraxerol acetate (3), β-sitosterol (4), stigmasterol (5), trans-ethyl caffeate, dracunculin (7), scoparone (8) and isoscopoletin (9) were isolated from an ethanolic extract of the roots of Artemisia incisa Pamp (Asteracae). The structures of the compounds were determined through IR, 1D NMR (1H NMR, 13C NMR) and 2D NMR (COSY, NOESY, HSQC and HMBC) analyses. Accurate mass analyses were done with EI-MS, ESI-MS and acid methanolysis of compound 1 followed by GS-MS studies. The relative stereochemistry of artemceramide-B was determined by comparing its specific rotation and spectroscopic data with the literature. Compounds 1-9 were tested for their anti-bacterial potential against five bacteria strains; Staphylococcus epidermidis, Staphylococcus aureus, Klebsiella pneumoniae, Bacillus subtilis and Escherichia coli. Compound 1 (new) (MIC: 0.0157, 0.0313 mg/mL) and 7 (MIC: 0.0815 , 1.000 mg/mL) showed excellent activities against S. epidermidis and S. aureus while compound 9 showed excellent activities (MIC: 0.0700 , 1.234, 1.890 and 2.286 mg/mL) against S. epidermidis,S. aureus, K. pneumoniae and E. coli, respectively. Compound 6 (MIC: 2.000 mg/mL) was found to be active against E. coli while neither of the compounds showed potential activity against B. subtilis

Enhanced attentional bias towards sexually explicit cues in individuals with and without compulsive sexual behaviours.

Compulsive sexual behaviour (CSB) is relatively common and has been associated with significant distress and psychosocial impairments. CSB has been conceptualized as either an impulse control disorder or a non-substance 'behavioural' addiction. Substance use disorders are commonly associated with attentional biases to drug cues which are believed to reflect processes of incentive salience. Here we assess male CSB subjects compared to age-matched male healthy controls using a dot probe task to assess attentional bias to sexually explicit cues. We show that compared to healthy volunteers, CSB subjects have enhanced attentional bias to explicit cues but not neutral cues particularly for early stimuli latency. Our findings suggest enhanced attentional bias to explicit cues possibly related to an early orienting attentional response. This finding dovetails with our recent observation that sexually explicit videos were associated with greater activity in a neural network similar to that observed in drug-cue-reactivity studies. Greater desire or wanting rather than liking was further associated with activity in this neural network. These studies together provide support for an incentive motivation theory of addiction underlying the aberrant response towards sexual cues in CSB.This is the published version of the manuscript. It is originally published by PLoS in PLoS ONE here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0105476

Jumping the Gun: Mapping Neural Correlates of Waiting Impulsivity and Relevance Across Alcohol Misuse.

BACKGROUND: Why do we jump the gun or speak out of turn? Waiting impulsivity has a preclinical basis as a predictor for the development of addiction. Here, we mapped the intrinsic neural correlates of waiting and dissociated it from stopping, both fundamental mechanisms of behavioral control. METHODS: We used a recently developed translational task to assess premature responding and assess response inhibition using the stop signal task. We mapped the neural correlates in 55 healthy volunteers using a novel multi-echo resting-state functional magnetic resonance imaging sequence and analysis, which robustly boosts signal-to-noise ratio. We further assessed 32 young binge drinkers and 36 abstinent subjects with alcohol use disorders. RESULTS: Connectivity of limbic and motor cortical and striatal nodes mapped onto a mesial-lateral axis of the subthalamic nucleus. Waiting impulsivity was associated with lower connectivity of the subthalamic nucleus with ventral striatum and subgenual cingulate, regions similarly implicated in rodent lesion studies. This network was dissociable from fast reactive stopping involving hyperdirect connections of the pre-supplementary area and subthalamic nucleus. We further showed that binge drinkers, like those with alcohol use disorders, had elevated premature responding and emphasized the relevance of this subthalamic network across alcohol misuse. Using machine learning techniques we showed that subthalamic connectivity differentiates binge drinkers and individuals with alcohol use disorders from healthy volunteers. CONCLUSIONS: We highlight the translational and clinical relevance of dissociable functional systems of cortical, striatal, and hyperdirect connections with the subthalamic nucleus in modulating waiting and stopping and their importance across dimensions of alcohol misuse.The study was funded by the Wellcome Trust Fellowship grant for VV (093705/Z/10/Z) and Cambridge NIHR Biomedical Research Centre. VV and NAH are Wellcome Trust (WT) intermediate Clinical Fellows. The BCNI is supported by a WT and MRC grant. ETB is employed part-time by the University of Cambridge and part-time by GSK PLC and is a shareholder of GSK. TWR is a consultant for Cambridge Cognition, Eli Lilly, GSK, Merck, Sharpe and Dohme, Lundbeck, Teva and Shire Pharmaceuticals. He is or has been in receipt of research grants from Lundbeck, Eli Lilly and GSK and is an editor for Springer-Verlag (Psychopharmacology). The remaining authors declare no competing financial interests.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.biopsych.2015.06.00

Fronto-striatal organization: Defining functional and microstructural substrates of behavioural flexibility.

Discrete yet overlapping frontal-striatal circuits mediate broadly dissociable cognitive and behavioural processes. Using a recently developed multi-echo resting-state functional MRI (magnetic resonance imaging) sequence with greatly enhanced signal compared to noise ratios, we map frontal cortical functional projections to the striatum and striatal projections through the direct and indirect basal ganglia circuit. We demonstrate distinct limbic (ventromedial prefrontal regions, ventral striatum - VS, ventral tegmental area - VTA), motor (supplementary motor areas - SMAs, putamen, substantia nigra) and cognitive (lateral prefrontal and caudate) functional connectivity. We confirm the functional nature of the cortico-striatal connections, demonstrating correlates of well-established goal-directed behaviour (involving medial orbitofrontal cortex - mOFC and VS), probabilistic reversal learning (lateral orbitofrontal cortex - lOFC and VS) and attentional shifting (dorsolateral prefrontal cortex - dlPFC and VS) while assessing habitual model-free (SMA and putamen) behaviours on an exploratory basis. We further use neurite orientation dispersion and density imaging (NODDI) to show that more goal-directed model-based learning (MBc) is also associated with higher mOFC neurite density and habitual model-free learning (MFc) implicates neurite complexity in the putamen. This data highlights similarities between a computational account of MFc and conventional measures of habit learning. We highlight the intrinsic functional and structural architecture of parallel systems of behavioural control.VV and NAH are Wellcome Trust (WT) intermediate Clinical Fellows. LM is in receipt of an MRC studentship. The BCNI is supported by a WT and MRC grant. ETB is employed part-time by the University of Cambridge and part-time by GSK PLC and is a shareholder of GSK. TWR is a consultant for Cambridge Cognition, Eli Lilly, GSK, Merck, Sharpe and Dohme, Lundbeck, Teva and Shire Pharmaceuticals. He is or has been in receipt of research grants from Lundbeck, Eli Lilly and GSK and is an editor for Springer-Verlag (Psychopharmacology). The remaining authors declare no competing financial interests. The study was funded by the Wellcome Trust Fellowship grant for VV (093705/Z/10/Z) and Cambridge NIHR Biomedical Research Centre.This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.cortex.2015.11.00

Effects of Veliparib on Microglial Activation and Functional Outcomes after Traumatic Brain Injury in the Rat and Pig.

The inflammation response induced by brain trauma can impair recovery. This response requires several hours to develop fully and thus provides a clinically relevant therapeutic window of opportunity. Poly(ADP-ribose) polymerase inhibitors suppress inflammatory responses, including brain microglial activation. We evaluated delayed treatment with veliparib, a poly(ADP-ribose) polymerase inhibitor, currently in clinical trials as a cancer therapeutic, in rats and pigs subjected to controlled cortical impact (CCI). In rats, CCI induced a robust inflammatory response at the lesion margins, scattered cell death in the dentate gyrus, and a delayed, progressive loss of corpus callosum axons. Pre-determined measures of cognitive and motor function showed evidence of attentional deficits that resolved after three weeks and motor deficits that recovered only partially over eight weeks. Veliparib was administered beginning 2 or 24 h after CCI and continued for up to 12 days. Veliparib suppressed CCI-induced microglial activation at doses of 3 mg/kg or higher and reduced reactive astrocytosis and cell death in the dentate gyrus, but had no significant effect on delayed axonal loss or functional recovery. In pigs, CCI similarly induced a perilesional microglial activation that was attenuated by veliparib. CCI in the pig did not, however, induce detectable persisting cognitive or motor impairment. Our results showed veliparib suppression of CCI-induced microglial activation with a delay-to-treatment interval of at least 24 h in both rats and pigs, but with no associated functional improvement. The lack of improvement in long-term recovery underscores the complexities in translating anti-inflammatory effects to clinically relevant outcomes

Measuring “waiting” impulsivity in substance addictions and binge eating disorder in a novel analogue of rodent serial reaction time task

Background Premature responding is a form of motor impulsivity that preclinical evidence has shown to predict compulsive drug seeking but has not yet been studied in humans. We developed a novel translation of the task, based on the rodent 5-choice serial reaction time task, testing premature responding in disorders of drug and natural food rewards. Methods Abstinent alcohol- (n = 30) and methamphetamine-dependent (n = 23) subjects, recreational cannabis users (n = 30), and obese subjects with (n = 30) and without (n = 30) binge eating disorder (BED) were compared with matched healthy volunteers and tested on the premature responding task. Results Compared with healthy volunteers, alcohol- and methamphetamine-dependent subjects and cannabis users showed greater premature responding with no differences observed in obese subjects with or without BED. Current smokers exhibited greater premature responding versus ex-smokers and nonsmokers. Alcohol-dependent subjects also had lower motivation for explicit monetary incentives. A Motivation Index correlated negatively with alcohol use and binge eating severity. Conclusions Premature responding on a novel translation of a serial reaction time task was more evident in substance use disorders but not in obese subjects with or without BED. Lower motivation for monetary incentives linked alcohol use and binge eating severity. Our findings add to understanding the relationship between drug and natural food rewards

Impaired decisional impulsivity in pathological videogamers

Abstract Background Pathological gaming is an emerging and poorly understood problem. Impulsivity is commonly impaired in disorders of behavioural and substance addiction, hence we sought to systematically investigate the different subtypes of decisional and motor impulsivity in a well-defined pathological gaming cohort. Methods Fifty-two pathological gaming subjects and age-, gender- and IQ-matched healthy volunteers were tested on decisional impulsivity (Information Sampling Task testing reflection impulsivity and delay discounting questionnaire testing impulsive choice), and motor impulsivity (Stop Signal Task testing motor response inhibition, and the premature responding task). We used stringent diagnostic criteria highlighting functional impairment. Results In the Information Sampling Task, pathological gaming participants sampled less evidence prior to making a decision and scored fewer points compared with healthy volunteers. Gaming severity was also negatively correlated with evidence gathered and positively correlated with sampling error and points acquired. In the delay discounting task, pathological gamers made more impulsive choices, preferring smaller immediate over larger delayed rewards. Pathological gamers made more premature responses related to comorbid nicotine use. Greater number of hours played also correlated with a Motivational Index. Greater frequency of role playing games was associated with impaired motor response inhibition and strategy games with faster Go reaction time. Conclusions We show that pathological gaming is associated with impaired decisional impulsivity with negative consequences in task performance. Decisional impulsivity may be a potential target in therapeutic management

Increased ventral striatal volume in college-aged binge drinkers

BACKGROUND Binge drinking is a serious public health issue associated with cognitive, physiological, and anatomical differences from healthy individuals. No studies, however, have reported subcortical grey matter differences in this population. To address this, we compared the grey matter volumes of college-age binge drinkers and healthy controls, focusing on the ventral striatum, hippocampus and amygdala. METHOD T1-weighted images of 19 binge drinkers and 19 healthy volunteers were analyzed using voxel-based morphometry. Structural data were also covaried with Alcohol Use Disorders Identification Test (AUDIT) scores. Cluster-extent threshold and small volume corrections were both used to analyze imaging data. RESULTS Binge drinkers had significantly larger ventral striatal grey matter volumes compared to controls. There were no between group differences in hippocampal or amygdalar volume. Ventral striatal, amygdalar, and hippocampal volumes were also negatively related to AUDIT scores across groups. CONCLUSIONS Our findings stand in contrast to the lower ventral striatal volume previously observed in more severe forms of alcohol use disorders, suggesting that college-age binge drinkers may represent a distinct population from those groups. These findings may instead represent early sequelae, compensatory effects of repeated binge and withdrawal, or an endophenotypic risk factor