Precision weighting of cortical unsigned prediction error signals benefits learning, is mediated by dopamine, and is impaired in psychosis.

Recent theories of cortical function construe the brain as performing hierarchical Bayesian inference. According to these theories, the precision of prediction errors plays a key role in learning and decision-making, is controlled by dopamine and contributes to the pathogenesis of psychosis. To test these hypotheses, we studied learning with variable outcome-precision in healthy individuals after dopaminergic modulation with a placebo, a dopamine receptor agonist bromocriptine or a dopamine receptor antagonist sulpiride (dopamine study n = 59) and in patients with early psychosis (psychosis study n = 74: 20 participants with first-episode psychosis, 30 healthy controls and 24 participants with at-risk mental state attenuated psychotic symptoms). Behavioural computational modelling indicated that precision weighting of prediction errors benefits learning in health and is impaired in psychosis. FMRI revealed coding of unsigned prediction errors, which signal surprise, relative to their precision in superior frontal cortex (replicated across studies, combined n = 133), which was perturbed by dopaminergic modulation, impaired in psychosis and associated with task performance and schizotypy (schizotypy correlation in 86 healthy volunteers). In contrast to our previous work, we did not observe significant precision-weighting of signed prediction errors, which signal valence, in the midbrain and ventral striatum in the healthy controls (or patients) in the psychosis study. We conclude that healthy people, but not patients with first-episode psychosis, take into account the precision of the environment when updating beliefs. Precision weighting of cortical prediction error signals is a key mechanism through which dopamine modulates inference and contributes to the pathogenesis of psychosis.

Model-Based Approach for Optimizing Study Design and Clinical Drug Performances of Extended-Release Formulations of Methylphenidate for the Treatment of ADHD.

Methylphenidate (MPH) is currently used to treat children with attention deficit hyperactivity disorder (ADHD). Several extended-release (ER) formulations characterized by a dual release process were developed to improve efficacy over an extended duration. In this study, a model-based approach using literature data was developed to: 1) evaluate the most efficient pharmacokinetic (PK) model to characterize the complex PK profile of MPH ER formulations; 2) provide PK endpoint metrics for comparing ER formulations; 3) define criteria for optimizing development of ER formulations using a convolution-based model linking in vitro release, in vivo release, and hour-by-hour behavioral ratings of ADHD symptoms; and 4) define an optimized trial design for assessing the activity of MPH in pediatric populations. The convolution-based model accurately described the complex PK profiles of a variety of ER MPH products, providing a natural framework for establishing an in vitro/in vivo correlation and for defining criteria for assessing comparative bioequivalence of MPH ER products.

Local membrane length conservation in two-dimensional vesicle simulation using a multicomponent lattice Boltzmann equation method.

We present a method for applying a class of velocity-dependent forces within a multicomponent lattice Boltzmann equation simulation that is designed to recover continuum regime incompressible hydrodynamics. This method is applied to the problem, in two dimensions, of constraining to uniformity the tangential velocity of a vesicle membrane implemented within a recent multicomponent lattice Boltzmann simulation method, which avoids the use of Lagrangian boundary tracers. The constraint of uniform tangential velocity is carried by an additional contribution to an immersed boundary force, which we derive here from physical arguments. The result of this enhanced immersed boundary force is to apply a physically appropriate boundary condition at the interface between separated lattice fluids, defined as that region over which the phase-field varies most rapidly. Data from this enhanced vesicle boundary method are in agreement with other data obtained using related methods [e.g., T. Krüger, S. Frijters, F. Günther, B. Kaoui, and J. Harting, Eur. Phys. J. 222, 177 (2013)10.1140/epjst/e2013-01834-y] and underscore the importance of a correct vesicle membrane condition.

Functional effects of dopamine transporter gene genotypes on in vivo dopamine transporter functioning: a meta-analysis.

Much psychiatric genetic research has focused on a 40-base pair variable number of tandem repeats (VNTR) polymorphism located in the 3'-untranslated region (3'UTR) of the dopamine active transporter (DAT) gene (SLC6A3). This variant produces two common alleles with 9- and 10-repeats (9R and 10R). Studies associating this variant with in vivo DAT activity in humans have had mixed results. We searched for studies using positron emission tomography (PET) or single-photon emission computed tomography (SPECT) to evaluate this association. Random effects meta-analyses assessed the association of the 3'UTR variant with DAT activity. We also evaluated heterogeneity among studies and evidence for publication bias. We found twelve studies comprising 511 subjects, 125 from PET studies and 386 from SPECT studies. The PET studies provided highly significant evidence that the 9R allele was associated with increased DAT activity in human adults. The SPECT studies were highly heterogeneous. As a group, they suggested no association between the 3'UTR polymorphism and DAT activity. When the analysis was limited to the most commonly used ligand, [123I]ß-CIT, stratification by affection status dramatically reduced heterogeneity and revealed a significant association of the 9R allele with increased DAT activity for healthy subjects. In humans, the 9R allele of the 3'UTR polymorphism of SLC6A3 regulates dopamine activity in the striatal brain regions independent of the presence of neuropsychiatric illness. Differences in study methodology account for the heterogeneous results across individual studies.

Multiple-component lattice Boltzmann equation for fluid-filled vesicles in flow.

We document the derivation and implementation of extensions to a two-dimensional, multicomponent lattice Boltzmann equation model, with Laplace law interfacial tension. The extended model behaves in such a way that the boundary between its immiscible drop and embedding fluid components can be shown to describe a vesicle of constant volume bounded by a membrane with conserved length, specified interface compressibility, bending rigidity, preferred curvature, and interfacial tension. We describe how to apply this result to several, independent vesicles. The extended scheme is completely Eulerian, and it represents a two-way coupled vesicle membrane and flow within a single framework. Unlike previous methods, our approach dispenses entirely with the need explicitly to track the membrane, or boundary, and makes no use whatsoever of computationally expensive and intricate interface tracking and remeshing. Validation data are presented, which demonstrate the utility of the method in the simulation of the flow of high volume fraction suspensions of deformable objects.

Multicomponent lattice Boltzmann equation method with a discontinuous hydrodynamic interface.

In the multicomponent lattice Boltzmann equation simulation method (MCLB), applied to the continuum regime of fluid flow, the finite width of the fluid-fluid interface introduces unphysical scales. We present a practical, robust, computationally efficient, and easy to implement solution to this problem which needs only low order interpolation to be stable and accurate and is applicable to any MCLB variant which uses a continuous phase field to distinguish between immiscible fluids with arrested coalescence. Our method extends the ideas of Kim and Pitsch, [Phys. Fluids 19, 108101 (2007)] and uses no external force distribution whatsoever to generate continuum interfacial physics, i.e., the Laplace law and no traction conditions on interfacial stresses. As such, it is amenable to the simplest form of Chapman-Enskog analysis used for lattice Boltzmann models. We assess our method and proceed to compare key results obtained with it against other equivalent data, obtained using the established continuum regime MCLB technique based upon the work of Lishchuk, Care, and Halliday, [Phys. Rev. E 67, 036701 (2003)] and Halliday, Hollis, and Care, [Phys. Rev. E 76, 026708 (2007)], quantifying performance in terms of the minimum feasible capillary available to simulation using that technique.

In silico multi-scale model of transport and dynamic seeding in a bone tissue engineering perfusion bioreactor.

Computer simulations can potentially be used to design, predict, and inform properties for tissue engineering perfusion bioreactors. In this work, we investigate the flow properties that result from a particular poly-L-lactide porous scaffold and a particular choice of perfusion bioreactor vessel design used in bone tissue engineering. We also propose a model to investigate the dynamic seeding properties such as the homogeneity (or lack of) of the cellular distribution within the scaffold of the perfusion bioreactor: a pre-requisite for the subsequent successful uniform growth of a viable bone tissue engineered construct. Flows inside geometrically complex scaffolds have been investigated previously and results shown at these pore scales. Here, it is our aim to show accurately that through the use of modern high performance computers that the bioreactor device scale that encloses a scaffold can affect the flows and stresses within the pores throughout the scaffold which has implications for bioreactor design, control, and use. Central to this work is that the boundary conditions are derived from micro computed tomography scans of both a device chamber and scaffold in order to avoid generalizations and uncertainties. Dynamic seeding methods have also been shown to provide certain advantages over static seeding methods. We propose here a novel coupled model for dynamic seeding accounting for flow, species mass transport and cell advection-diffusion-attachment tuned for bone tissue engineering. The model highlights the timescale differences between different species suggesting that traditional homogeneous porous flow models of transport must be applied with caution to perfusion bioreactors. Our in silico data illustrate the extent to which these experiments have the potential to contribute to future design and development of large-scale bioreactors.

Examining the nature of the comorbidity between pediatric attention deficit/hyperactivity disorder and post-traumatic stress disorder.

OBJECTIVE: This study sought to address the link between attention deficit/hyperactivity disorder (ADHD) and post-traumatic stress disorder (PTSD) in youth by providing a comprehensive comparison of clinical correlates of ADHD subjects with and without PTSD across multiple non-overlapping domains of functioning and familial patterns of transmission. METHOD: Participants were 271 youths with ADHD and 230 controls without ADHD of both sexes along with their siblings. Participants completed a large battery of measures designed to assess psychiatric comorbidity, psychosocial, educational, and cognitive parameters. RESULTS: Post-traumatic stress disorder was significantly higher in ADHD probands vs. controls (5.2% vs. 1.7%, χ(2) (1) = 4.36, P = 0.04). Irrespective of the comorbidity with PTSD, ADHD subjects had similar ages at onset of ADHD, similar type and mean number of ADHD symptoms, and similar ADHD-associated impairments. PTSD in ADHD probands was significantly associated with a higher risk of psychiatric hospitalization, school impairment, poorer social functioning and higher prevalences of mood, conduct disorder, and anxiety disorders. The mean onset of PTSD (12.6 years) was significantly later than that of ADHD and comorbid disorders (all P < 0.05). Siblings of ADHD and ADHD + PTSD probands had higher prevalences of ADHD vs. siblings of controls (35% vs. 18%, z = 4.00, P < 0.001 and 67% vs. 18%, z = 4.02, P < 0.001 respectively) and siblings of ADHD+PTSD probands had a significantly higher prevalence of PTSD compared with the siblings of ADHD and control probands (20% vs. 3% and 3%, z = 2.99, P = 0.003 and z = 2.07, P = 0.04 respectively). CONCLUSION: Findings indicate that the comorbidity with PTSD in ADHD leads to greater clinical severity as regards psychiatric comorbidity and psychosocial dysfunction. ADHD is equally familial in the presence of PTSD in the proband indicating that their co-occurrence is not owing to diagnostic error.

Multi-scale interaction of particulate flow and the artery wall.

We discuss, from the perspective of basic science, the physical and biological processes which underlie atherosclerotic (plaque) initiation at the vascular endothelium, identifying the widely separated spatial and temporal scales which participate. We draw on current, related models of vessel wall evolution, paying particular attention to the role of particulate flow (blood is not a continuum fluid), and proceed to propose, then validate all the key components in a multiply-coupled, multi-scale modeling strategy (in qualitative terms only, note). Eventually, this strategy should lead to a quantitative, patient-specific understanding of the coupling between particulate flow and the endothelial state.

Zenithal bistable device: Comparison of modeling and experiment.

A comparative modeling and experimental study of the zenithal bistable liquid crystal device is presented. A dynamic Landau de Gennes theory of nematic liquid crystals is solved numerically to model the electric field induced latching of the device and the results are compared with experimental measurements and theoretical approximations. The study gives a clear insight into the latching mechanism dynamics and enables the dependence of the device latching on both material parameters and surface shape to be determined. Analytical approximation highlights a route to optimize material selection in terms of latching voltages and the numerical model, which includes an accurate surface representation, recovers the complex surface shape effects. Predictions of device performance are presented as a function of both surface anchoring strength and surface shape and grating pitch. A measurement of the homeotropic anchoring energy has been undertaken by comparing the voltage response as a function of cell gap; we find the homeotropic anchoring energies can be varied in the range 0.5 to 4 ( 10^{-4} J m^{-2} ).

Lattice Boltzmann equation method for multiple immiscible continuum fluids.

This paper generalizes the two-component algorithm of Sec. , extending it, in Sec. , to describe N>2 mutually immiscible fluids in the isothermal continuum regime. Each fluid has an independent interfacial tension. While retaining all its computational advantages, we remove entirely the empiricism associated with contact behavior in our previous multiple immiscible fluid models [M. M. Dupin, Phys. Rev. E 73, 055701(R) (2006); Med. Eng. Phys. 28, 13 (2006)] while solidifying the physical foundations. Moreover, the model relies upon a fluid-fluid segregation which is simpler, computationally faster, more free of artifacts (i.e., the interfacial microcurrent), and upon an interface-inducing force distribution which is analytic. The method is completely symmetric between any numbers of immiscible fluids and stable over a wide range of directly input interfacial tension. We present data on the steady-state properties of multiple interface model, which are in good agreement with theory [R. E. Johnson and S. S. Sadhal, Annu. Rev. Fluid Mech. 17, 289 (1985)], specifically on the shapes of multidrop systems. Section is an analysis of the kinetic and continuum-scale descriptions of the underlying two-component lattice Boltzmann model for immiscible fluids, extendable to more than two immiscible fluids. This extension requires (i) the use of a more local kinetic equation perturbation which is (ii) free from a reliance on measured interfacial curvature. It should be noted that viewed simply as a two-component method, the continuum algorithm is inferior to our previous methods, reported by Lishchuk [Phys. Rev. E 67, 036701 (2003)] and Halliday [Phys. Rev. E 76, 026708 (2007)]. Greater stability and parameter range is achieved in multiple drop simulations by using the forced multi-relaxation-time lattice Boltzmann method developed, along with (for completeness) a forced exactly incompressible Bhatnagar-Gross-Krook lattice Boltzmann model, in the Appendix. These appended schemes closely follow those developed by Guo [Phys. Rev. E 65, 046308 (2002)] for the single-relaxation-time scheme.

Validation of multicomponent lattice Boltzmann equation simulations using theoretical calculations of immiscible drop shape.

Quantitative comparison between the measured deformation of a neutrally buoyant drop, obtained with an appropriately conceived three-dimensional, multicomponent lattice Boltzmann equation simulation methods for continuum multicomponent hydrodynamics [Phys. Rev. E 76, 026708 (2007); 76, 026709 (2007)], are shown to be in agreement with the theoretical predictions of Taylor and Acrivos [J. Fluid. Mech. 18(3), 466 (1964)].

Lattice Boltzmann scheme for modeling liquid-crystal dynamics: Zenithal bistable device in the presence of defect motion.

A lattice Boltzmann scheme is presented which recovers the dynamics of nematic and chiral liquid crystals; the method essentially gives solutions to the Qian-Sheng [Phys. Rev. E 58, 7475 (1998)] equations for the evolution of the velocity and tensor order-parameter fields. The resulting algorithm is able to include five independent Leslie viscosities, a Landau-deGennes free energy which introduces three or more elastic constants, a temperature dependent order parameter, surface anchoring and viscosity coefficients, flexoelectric and order electricity, and chirality. When combined with a solver for the Maxwell equations associated with the electric field, the algorithm is able to provide a full "device solver" for a liquid crystal display. Coupled lattice Boltzmann schemes are used to capture the evolution of the fast momentum and slow director motions in a computationally efficient way. The method is shown to give results in close agreement with analytical results for a number of validating examples. The use of the method is illustrated through the simulation of the motion of defects in a zenithal bistable liquid crystal device.

Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders.

OBJECTIVE: To test the hypothesis that atomoxetine does not significantly worsen tic severity relative to placebo in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid tic disorders. METHODS: Study subjects were 7 to 17 years old, met Diagnostic and Statistical Manual of Mental Disorders-IV criteria for ADHD, and had concurrent Tourette syndrome or chronic motor tic disorder. Patients were randomly assigned to double-blind treatment with placebo (n = 72) or atomoxetine (0.5 to 1.5 mg/kg/day, n = 76) for up to 18 weeks. RESULTS: Atomoxetine treatment was associated with greater reduction of tic severity at endpoint relative to placebo, approaching significance on the Yale Global Tic Severity Scale total score (-5.5 +/- 6.9 vs -3.0 +/- 8.7, p = 0.063) and Tic Symptom Self-Report total score (-4.7 +/- 6.5 vs -2.9 +/- 5.2, p = 0.095) and achieving significance on the Clinical Global Impressions (CGI) tic/neurologic severity scale score (-0.7 +/- 1.2 vs -0.1 +/- 1.0, p = 0.002). Atomoxetine patients also showed greater improvement on the ADHD Rating Scale total score (-10.9 +/- 10.9 vs -4.9 +/- 10.3, p < 0.001) and CGI severity of ADHD/psychiatric symptoms scale score (-0.8 +/- 1.1 vs -0.3 +/- 1.0, p = 0.015). Discontinuation rates were not significantly different between treatment groups. Atomoxetine patients had greater increases in heart rate and decreases of body weight, and rates of treatment-emergent decreased appetite and nausea were higher. No other clinically relevant treatment differences were seen in any other vital sign, adverse event, or electrocardiographic or laboratory measures. CONCLUSIONS: Atomoxetine did not exacerbate tic symptoms. Rather, there was some evidence of reduction in tic severity with a significant reduction of attention deficit/hyperactivity disorder symptoms. Atomoxetine treatment appeared safe and well tolerated.

A many-component lattice Boltzmann equation simulation for transport of deformable particles.

We review the analysis of single and N-component lattice Boltzmann methods for fluid flow simulation. Results are presented for the emergent pressure field of a single phase incompressible liquid flowing over a backward-facing step, at moderate Reynolds Number, which is compared with the experimental data of Denham & Patrick (1974 Trans. IChE 52, 361-367). We then access the potential of the N-component method for transport of high volume fraction suspensions of deformable particles in pressure-driven flow. The latter are modelled as incompressible, closely packed liquid drops. We demonstrate the technique by investigating the particles' transverse migration in a uniform shear ('lift'), and profile blunting and chaining.

Parsing pediatric bipolar disorder from its associated comorbidity with the disruptive behavior disorders.

The unique pattern of comorbidity found in pediatric mania greatly complicates accurate diagnosis, the course of the disorder, and its treatment. The pattern of comorbidity is unique by adult standards, especially its overlap with attention-deficit/hyperactivity disorder (ADHD), aggression, and conduct disorder. Clinically, symptoms of mania have been discounted as severe ADHD or ignored in the context of aggressive conduct disorder. This atypicality may lead to neglect of the mood component. The addition of high rates of additional disorders contributes to the severe morbidity, dysfunction, and incapacitation frequently observed in these children. A comprehensive approach to diagnostic evaluation is the keystone to establishing an effective treatment program because response to treatment differs with individual disorders. Recognition of the multiplicity of disorders guides therapeutic options in these often refractory conditions. What was previously considered refractory ADHD, oppositionality, aggression, and conduct disorder may respond after mood stabilization. We review these issues in this article.

Impact of tic disorders on ADHD outcome across the life cycle: findings from a large group of adults with and without ADHD.

OBJECTIVE: The impact of tic disorders on the outcome of attention deficit hyperactivity disorder (ADHD) remains a subject of high scientific and clinical interest. To evaluate the impact of comorbid ADHD and tic disorders from a lifespan perspective, the authors systematically examined data from adults with and without ADHD. METHOD: They comprehensively evaluated 312 consecutively referred adults with ADHD and 252 comparison subjects without ADHD. Tic disorders were characterized along with a wide range of neuropsychiatric correlates, including other comorbid disorders as well as indexes of function in the domains of school, cognition, and interpersonal functioning. RESULTS: A significantly greater proportion of adults with ADHD (12%) than those without ADHD (4%) had tic disorders. Tic disorders followed a mostly remitting course and had little impact on functional capacities. In addition, tic disorders were not associated with stimulant use. CONCLUSIONS: These findings in adults with ADHD confirm and extend previous findings in young subjects with ADHD, documenting that although individuals with ADHD are at greater risk for tic disorders, the presence of tic disorders has a limited impact on ADHD outcome.

A controlled clinical trial of bupropion for attention deficit hyperactivity disorder in adults.

OBJECTIVE: Despite the increasing recognition of attention deficit hyperactivity disorder (ADHD) in adults, there is a paucity of controlled pharmacological trials demonstrating the effectiveness of compounds used in treatment, particularly nonstimulants. The authors report results from a controlled investigation to determine the anti-ADHD efficacy of bupropion in adult patients with DSM-IV ADHD. METHOD: This was a double-blind, placebo-controlled, randomized, parallel, 6-week trial comparing patients receiving sustained-release bupropion (up to 200 mg b.i.d.) (N=21) to patients receiving placebo (N=19). The authors used standardized structured psychiatric instruments for diagnosis of ADHD. To measure improvement, they used separate assessments of ADHD, depression, and anxiety symptoms at baseline and each weekly visit. RESULTS: Of the 40 subjects (55% male) enrolled in the study, 38 completed the study. Bupropion treatment was associated with a significant change in ADHD symptoms at the week-6 endpoint (42% reduction), which exceeded the effects of placebo (24% reduction). In analyses using a cutoff of 30% or better reduction to denote response, 76% of the subjects receiving bupropion improved, compared to 37% of the subjects receiving placebo. Similarly, in analyses using Clinical Global Impression scale scores, 52% of the subjects receiving bupropion reported being "much improved" to "very improved," compared to 11% of the subjects receiving placebo. CONCLUSIONS: These results indicate a clinically and statistically significant effect of bupropion in improving ADHD in adults. The results suggest a therapeutic role for bupropion in the armamentarium of agents for ADHD in adults, while further validating the continuity of pharmacological responsivity of ADHD across the lifespan.