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Richiardi J.,Ecole Polytechnique Federale de Lausanne | Richiardi J.,University of Geneva | Achard S.,CNRS GIPSA Laboratory | Bullmore E.,University of Cambridge | And 3 more authors.
Proceedings - International Workshop on Pattern Recognition in NeuroImaging, PRNI 2011 | Year: 2011

Qualitative and quantitative description of functional connectivity graphs using graph attributes is of great interest to neuroscience, and has led to remarkable insights in the field. However, the statistical techniques used have generally been limited to whole-group, post-hoc studies. In this paper, we propose instead a novel approach to perform predictive inference on single subjects. It is based on a lossy embedding of connectivity graphs into a vector space using graph and vertex attributes, followed by the use of statistical machine learning to build a predictive model. The feature space proposed is easily interpretable for neuroscientists, and we illustrate the technique by revealing resting-state difference between young and elderly subjects. © 2011 IEEE.

Fornito A.,University of Cambridge | Fornito A.,University of Melbourne | Bullmore E.T.,University of Cambridge | Bullmore E.T.,GSK Clinical Unit Cambridge
Current Opinion in Psychiatry | Year: 2010

Purpose of review Resting-state functional MRI (rs-fMRI) is an increasingly popular technique for studying brain dysfunction in psychiatric patients, and is widely assumed to measure intrinsic properties of functional brain organization. Here, we review rs-fMRI studies of psychiatric populations and consider how recent evidence concerning the neuronal basis, behavioural relevance, and the stability of rs-fMRI measures can inform and constrain interpretation of findings obtained using case-control designs. Recent findings A range of rs-fMRI measures have been applied to different patient groups, although the findings have not always been consistent. The large-scale organization of rs-fMRI networks is robust and reproducible, and rs-fMRI measures show correlations with behavioural phenotypes relevant to psychiatry. However, evidence that such measures are also influenced by preceding psychological states and contexts, as well as individual variations in physiological arousal, may help to explain inconsistent findings in case-control comparisons. Summary rs-fMRI measures show both stable and dynamic properties, the nature of which are only beginning to be uncovered. As such, interpreting significant differences between patients and controls on rs-fMRI measures as evidence for alterations in intrinsic functional brain organization should be done cautiously. Better understanding of the relationship between stable and transient aspects of spontaneous brain dynamics will be necessary to constrain interpretation of case-control studies and inform pathophysiological models. © 2010 Wolters Kluwer Health π Lippincott Williams & Wilkins 0951-7367.

Nathan P.J.,GSK Clinical Unit Cambridge | Nathan P.J.,University of Cambridge | Watson J.,Glaxosmithkline | Lund J.,Glaxosmithkline | And 15 more authors.
International Journal of Neuropsychopharmacology | Year: 2013

Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M1 receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M1 receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M1 receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M1 receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease. © 2012 CINP.

Ziauddeen H.,GSK Clinical Unit Cambridge | Ziauddeen H.,University of Cambridge | Chamberlain S.R.,GSK Clinical Unit Cambridge | Chamberlain S.R.,University of Cambridge | And 21 more authors.
Molecular Psychiatry | Year: 2013

The opioid system is implicated in the hedonic and motivational processing of food, and in binge eating, a behaviour strongly linked to obesity. The aim of this study was to evaluate the effects of 4 weeks of treatment with the mu-opioid receptor antagonist GSK1521498 on eating behaviour in binge-eating obese subjects. Adults with body mass index ≥30 kg m -2 and binge eating scale scores ≥19 received 1-week single-blind placebo run-in, and were then randomized to 28 days with either 2 mg day -1 GSK1521498, 5 mg day -1 GSK1521498 or placebo (N=21 per arm) in a double-blind parallel group design. The outcome measures were body weight, fat mass, hedonic and consummatory eating behaviour during inpatient food challenges, safety and pharmacokinetics. The primary analysis was the comparison of change scores in the higher-dose treatment group versus placebo using analysis of covariance at each relevant time point. GSK1521498 (2 mg and 5 mg) was not different from placebo in its effects on weight, fat mass and binge eating scores. However, compared with placebo, GSK1521498 5 mg day -1 caused a significant reduction in hedonic responses to sweetened dairy products and reduced calorific intake, particularly of high-fat foods during ad libitum buffet meals, with some of these effects correlating with systemic exposure of GSK1521498. There were no significant effects of GSK1521498 2 mg day -1 on eating behaviour, indicating dose dependency of pharmacodynamics. GSK1521498 was generally well tolerated and no previously unidentified safety signals were detected. The potential for these findings to translate into clinically significant effects in the context of binge eating and weight regain prevention requires further investigation. © 2013 Macmillan Publishers Limited.

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