The relative balance of goal-directed and habitual behaviours in obsessive-compulsive disorder

Our decisions are based on parallel and competing systems of goal-directed and habitual learning, systems which can be impaired in pathological behaviours. Here we focus on the influence of motivation and compare reward and loss outcomes in subjects with obsessive-compulsive disorder (OCD) on model-based goal-directed and model-free habitual behaviours using the two-step task. We further investigate the relationship with acquisition learning using a one-step probabilistic learning task. Forty-eight OCD subjects and 96 healthy volunteers were tested on a reward and 30 OCD subjects and 53 healthy volunteers on the loss version of the two-step task. Thirty-six OCD subjects and 72 healthy volunteers were also tested on a one-step reversal task. OCD subjects compared with healthy volunteers were less goal oriented (model-based) and more habitual (model-free) to reward outcomes with a shift towards greater model-based and lower habitual choices to loss outcomes. OCD subjects also had enhanced acquisition learning to loss outcomes on the one-step task, which correlated with goal-directed learning in the two-step task. OCD subjects had greater stay behaviours or perseveration in the one-step task irrespective of outcome. Compulsion severity was correlated with habitual learning in the reward condition. Obsession severity was correlated with greater switching after loss outcomes. In healthy volunteers, we further show that greater reward magnitudes are associated with a shift towards greater goal-directed learning further emphasizing the role of outcome salience. Our results highlight an important influence of motivation on learning processes in OCD and suggest that distinct clinical strategies based on valence may be warranted.The study was funded through a Wellcome Trust Intermediate Clinical Fellowship for VV (093705/Z/10/Z).This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/tp.2015.16

Photoswitchable peptide-based ‘on-off’ biosensor for electrochemical detection and control of protein-protein interactions

Neuronal nitric oxide synthase (nNOS) is an enzyme responsible for catalyzing the production of the crucial cellular signalling molecule, nitric oxide (NO), through its interaction with the PDZ domain of α-syntrophin protein. In this study, a novel light-driven photoswitchable peptide-based biosensor, modelled on the nNOS β-finger, is used to detect and control its interaction with α-syntrophin. An azobenzene photoswitch incorporated into the peptide backbone allows reversible switching between a trans photostationary state devoid of secondary structure, and a cis photostationary state possessing a well-defined antiparallel β-strand geometry, as revealed by molecular modelling. Electrochemical impedance spectroscopy (EIS) is used to successfully detect the interaction between the gold electrode bound peptide in its cis photostationary state and a wide range of concentrations of α-syntrophin protein, highlighting both the qualitative and quantitative properties of the sensor. Furthermore, EIS demonstrates that the probe in its random trans photostationary state does not bind to the target protein. The effectiveness of the biosensor is further endorsed by the high thermal stability of the photostationary state of the cis-isomer, and the ability to actively control biomolecular interactions using light. This approach allows detection and control of binding to yield a regenerable on-off biosensor.John R.Horsley, Jingxian Yu, Kate L.Wegener, Christian Hoppmann, Karola Rück-Braun, Andrew D.Abel

Counting Points on Genus 2 Curves with Real Multiplication

We present an accelerated Schoof-type point-counting algorithm for curves of genus 2 equipped with an efficiently computable real multiplication endomorphism. Our new algorithm reduces the complexity of genus 2 point counting over a finite field (\F_{q}) of large characteristic from (\widetilde{O}(\log^8 q)) to (\widetilde{O}(\log^5 q)). Using our algorithm we compute a 256-bit prime-order Jacobian, suitable for cryptographic applications, and also the order of a 1024-bit Jacobian

Amicable pairs and aliquot cycles for elliptic curves

An amicable pair for an elliptic curve E/Q is a pair of primes (p,q) of good reduction for E satisfying #E(F_p) = q and #E(F_q) = p. In this paper we study elliptic amicable pairs and analogously defined longer elliptic aliquot cycles. We show that there exist elliptic curves with arbitrarily long aliqout cycles, but that CM elliptic curves (with j not 0) have no aliqout cycles of length greater than two. We give conjectural formulas for the frequency of amicable pairs. For CM curves, the derivation of precise conjectural formulas involves a detailed analysis of the values of the Grossencharacter evaluated at a prime ideal P in End(E) having the property that #E(F_P) is prime. This is especially intricate for the family of curves with j = 0.Comment: 53 page

D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.2018-05-0

Parity of bound dipole states in 208Pb

The parities of eleven J=1 levels in 208Pb were determined by nuclear resonance fluorescence scattering of linearly polarized photons. A new 1+ level at Ex=5.846 MeV with Gamma 02 / Gamma =1.2±0.4 eV was found. This level can probably be identified with the theoretically predicted isoscalar 1+ state in 208Pb. All other bound dipole states below 7 MeV with Gamma 02 / Gamma >1.5 eV have negative parity. The 1- assignment to the 4.842-MeV level is of special significance because of previous conflicting results about its parity

Familial Risks of Tourette Syndrome and Chronic Tic Disorders. A Population-Based Cohort Study.

The Tourette Syndrome Association, IncThe Swedish Council for Working Life and Social ResearchThe Swedish Research CouncilManuscrip

Disorders of compulsivity: a common bias towards learning habits.

Why do we repeat choices that we know are bad for us? Decision making is characterized by the parallel engagement of two distinct systems, goal-directed and habitual, thought to arise from two computational learning mechanisms, model-based and model-free. The habitual system is a candidate source of pathological fixedness. Using a decision task that measures the contribution to learning of either mechanism, we show a bias towards model-free (habit) acquisition in disorders involving both natural (binge eating) and artificial (methamphetamine) rewards, and obsessive-compulsive disorder. This favoring of model-free learning may underlie the repetitive behaviors that ultimately dominate in these disorders. Further, we show that the habit formation bias is associated with lower gray matter volumes in caudate and medial orbitofrontal cortex. Our findings suggest that the dysfunction in a common neurocomputational mechanism may underlie diverse disorders involving compulsion.This study was funded by the WT fellowship grant for VV (093705/Z/ 10/Z) and Cambridge NIHR Biomedical Research Centre. VV and NAH are Wellcome Trust (WT) intermediate Clinical Fellows. YW is supported by the Fyssen Fondation and MRC Studentships. PD is supported by the Gatsby Charitable Foundation. JEG has received grants from the National Institute of Drug Abuse and the National Center for Responsible Gaming. TWR and BJS are supported on a WT Programme Grant (089589/Z/09/Z). The BCNI is supported by a WT and MRC grant.This is the final published version. It's also available from Molecular Psychiatry at http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201444a.html

Fusicoccin Counteracts the Toxic Effect of Cadmium on the Growth of Maize Coleoptile Segments

The effects of cadmium (Cd; 0.1–1000 μM) and fusicoccin (FC) on growth, Cd2+ content, and membrane potential (Em) in maize coleoptile segments were studied. In addition, the Em changes and accumulation of Cd and calcium (Ca) in coleoptile segments treated with Cd2+ combined with 1 μM FC or 30 mM tetraethylammonium (TEA) chloride (K+-channel blocker) were also determined. In this study, the effects of Ca2+-channel blockers [lanthanum (La) and verapamil (Ver)] on growth and content of Cd2+ and Ca2+ in coleoptile segments were also investigated. It was found that Cd at high concentrations (100 and 1000 μM) significantly inhibited endogenous growth of coleoptile segments and simultaneously measured proton extrusion. FC combined with Cd2+ counteracted the toxic effect of Cd2+ on endogenous growth and significantly decreased Cd2+ content (not the case for Cd2+ at the highest concentration) in coleoptile segments. Addition of Cd to the control medium caused depolarization of Em, the extent of which was dependent on Cd concentration and time of treatment with Cd2+. Hyperpolarization of Em induced by FC was suppressed in the presence of Cd2+ at 1000 μM but not Cd2+ at 100 μM. It was also found that treatment of maize coleoptile segments with 30 mM TEA chloride caused hyperpolarization of Em and decreased Cd2+ content in coleoptile segments, suggesting that, in the same way as for FC, accumulation of Cd2+ was dependent on plasma membrane (PM) hyperpolarization. Similar to FC, TEA chloride also decreased Ca2+ content in coleoptile segments. La and Ver combined with Cd2+ (100 μM) significantly decreased Cd content in maize coleoptile segments, but only La completely abolished the toxic effect of Cd2+ on endogenous growth and growth in the presence of FC. Taken together, these results suggest that the mechanism by which FC counteracts the toxic effect of Cd2+ (except at 1000 μM Cd2+) on the growth of maize coleoptile segments involves both stimulation of PM H+-ATPase activity by FC as well as Cd2+-permeable, voltage-dependent Ca channels, which are blocked by FC and TEA chloride-induced PM hyperpolarization

Quantitative aortography for assessment of aortic regurgitation in the era of percutaneous aortic valve replacement

Paravalvular leak (PVL) is a shortcoming that can erode the clinical benefits of transcatheter valve replacement (TAVR) and therefore a readily applicable method (aortography) to quantitate PVL objectively and accurately in the interventional suite is appealing to all operators. The ratio between the areas of the time-density curves in the aorta and left ventricular outflow tract (LVOT-AR) defines the regurgitation fraction (RF). This technique has been validated in a mock circulation; a single injection in diastole was further tested in porcine and ovine models. In the clinical setting, LVOT-AR was compared with trans-thoracic and trans-oesophageal echocardiography and cardiac magnetic resonance imaging. LVOT-AR > 17% discriminates mild from moderate aortic regurgitation on echocardiography and confers a poor prognosis in multiple registries, and justifies balloon post-dilatation. The LVOT-AR differentiates the individual performances of many old and novel devices and is being used in ongoing randomized trials and registries