Impulsivity in disorders of food and drug misuse.

BACKGROUND: Evidence suggests some overlap between the pathological use of food and drugs, yet how impulsivity compares across these different clinical disorders remains unclear. Substance use disorders are commonly characterized by elevated impulsivity, and impulsivity subtypes may show commonalities and differences in various conditions. We hypothesized that obese subjects with binge-eating disorder (BED) and abstinent alcohol-dependent cohorts would have relatively more impulsive profiles compared to obese subjects without BED. We also predicted decision impulsivity impairment in obesity with and without BED. METHOD: Thirty obese subjects with BED, 30 without BED and 30 abstinent alcohol-dependent subjects and age- and gender-matched controls were tested on delay discounting (preference for a smaller immediate reward over a larger delayed reward), reflection impulsivity (rapid decision making prior to evidence accumulation) and motor response inhibition (action cancellation of a prepotent response). RESULTS: All three groups had greater delay discounting relative to healthy volunteers. Both obese subjects without BED and alcohol-dependent subjects had impaired motor response inhibition. Only obese subjects without BED had impaired integration of available information to optimize outcomes over later trials with a cost condition. CONCLUSIONS: Delay discounting appears to be a common core impairment across disorders of food and drug intake. Unexpectedly, obese subjects without BED showed greater impulsivity than obese subjects with BED. We highlight the dissociability and heterogeneity of impulsivity subtypes and add to the understanding of neurocognitive profiles across disorders involving food and drugs. Our results have therapeutic implications suggesting that disorder-specific patterns of impulsivity could be targeted.V.V. is a Wellcome Trust Intermediate Fellow in Clinical Neurosciences (Wellcome Trust grant no. WT093705MA). Y.W. is supported by the Fyssen Fondation. N.A.H. is a Wellcome Trust Intermediate Fellow in Clinical Neurosciences. The BCNI is supported by both the Wellcome Trust and Medical Research Council.This is the accepted manuscript. The final version is available from CUP at http://dx.doi.org/10.1017/S003329171400183

"New Leadership", Leader-Member exchange And Commitment To Change: The Case Of Higher Education In Malaysia.

Human resource management faces challenges of bringing better fitted workers into the organizations and of meeting the workers' needs and expectations

Use of mRNA- and protein-destabilizing elements to develop a highly responsive reporter system

Reporter assays are widely used in applications that require measurement of changes in gene expression over time (e.g. drug screening). With standard reporter vectors, the measurable effect of a treatment or compound (altered reporter activity) is substantially diluted and delayed, compared with its true effect (altered transcriptional activity). This problem is caused by the relatively long half-lives of both the reporter protein and its mRNA. As a result, the activities of compounds, ligands or treatments that have a relatively minor effect, or a substantial but transient effect, often remain undetected. To circumvent this problem, we introduced modular protein- and mRNA-destabilizing elements into a range of commonly used reporters. Our data show that both elements are required for maximal responses to both increases and decreases in transcriptional activity. The double-destabilized reporter vectors showed markedly improved performance in drug screening, kinetic assays and dose–response titrations

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

Biases in the Explore-Exploit Tradeoff in Addictions: The Role of Avoidance of Uncertainty.

We focus on exploratory decisions across disorders of compulsivity, a potential dimensional construct for the classification of mental disorders. Behaviors associated with the pathological use of alcohol or food, in alcohol use disorders (AUD) or binge-eating disorder (BED), suggest a disturbance in explore-exploit decision-making, whereby strategic exploratory decisions in an attempt to improve long-term outcomes may diminish in favor of more repetitive or exploitatory choices. We compare exploration vs exploitation across disorders of natural (obesity with and without BED) and drug rewards (AUD). We separately acquired resting state functional MRI data using a novel multi-echo planar imaging sequence and independent components analysis from healthy individuals to assess the neural correlates underlying exploration. Participants with AUD showed reduced exploratory behavior across gain and loss environments, leading to lower-yielding exploitatory choices. Obese subjects with and without BED did not differ from healthy volunteers but when compared with each other or to AUD subjects, BED had enhanced exploratory behaviors particularly in the loss domain. All subject groups had decreased exploration or greater uncertainty avoidance to losses compared with rewards. More exploratory decisions in the context of reward were associated with frontal polar and ventral striatal connectivity. For losses, exploration was associated with frontal polar and precuneus connectivity. We further implicate the relevance and dimensionality of constructs of compulsivity across disorders of both natural and drug rewards.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. LSM is in receipt of an MRC studentship. The BCNI is supported by a WT and MRC grant. MF is funded by NIMH and NSF grants and is consultant for Hoffman LaRoche pharmaceuticals. The remaining authors declare no competing financial interests.This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/npp.2015.20

Habit reversal therapy in obsessive compulsive related disorders : A systematic review of the evidence and consort evaluation of randomized controlled trials

Background: Habit Reversal Therapy (HRT) has long been used in the treatment of Tourette Syndrome and Tic Disorders. It has more recently been used to treat Trichotillomania and skin picking behaviors, both considered as Obsessive Compulsive Related Disorders (OCRD). Objectives: This literature review sought to establish and quality assess the existing randomized controlled trial evidence supporting the use of HRT in the DSM-5 family of OCRDs. Search Methods: EMBASE, PsycINFO, PubMed, and Cochrane databases were searched for key terms relating to each OCRD (as classified in the DSM-5), and HRT. Selection Criteria: Titles and abstracts were screened, and any literature matching pre-specified criteria were then selected to be reviewed further. Of these, 8 Randomized Controlled Trials (RCT) relating to Trichotillomania, and 2 RCTs relating to Excoriation Disorder, were extracted and reviewed against the 2010 Consolidating Standards of Reporting Trials (CONSORT) statement. Results: The review identified 10 RCTs of HRT, but these were limited to patients with a primary diagnosis of Trichotillomania or “excoriation behavior,” only. There were some reports of the use of HRT in Tourette Syndrome or Tic Disorder with secondary OCD, but the OCD symptoms were not reliably reported on. Conclusion: There is a gap in the current literature regarding the use of HRT in the DSM-5 OCRDs. In those RCTs that have been reported, the quality of study methodology was questionable as evaluated by CONSORT criteria. The implications of these findings are discussed, and suggestions are made for future research.Peer reviewe