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.

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.

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.

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)].

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.

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.

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.

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.

Psychoactive substance use disorders in adults with attention deficit hyperactivity disorder (ADHD): effects of ADHD and psychiatric comorbidity.

OBJECTIVE: The authors evaluated the association between attention deficit hyperactivity disorder (ADHD) and psychoactive substance use disorders in adults with ADHD, attending to comorbidity with mood, anxiety, and antisocial disorders. It was hypothesized that psychiatric comorbidity would be a risk factor for psychoactive substance use disorders. METHOD: Findings for 120 referred adults with a clinical diagnosis of childhood-onset ADHD were compared with those for non-ADHD adult comparison subjects (N = 268). All childhood and adult diagnoses were obtained by structured psychiatric interviews for DSM-III-R. RESULTS: There was a significantly higher lifetime risk for psychoactive substance use disorders in the ADHD adults than in the comparison subjects (52% versus 27%). Although the two groups did not differ in the rate of alcohol use disorders, the ADHD adults had significantly higher rates of drug and drug plus alcohol use disorders than the comparison subjects. ADHD significantly increased the risk for substance use disorders independently of psychiatric comorbidity. Antisocial disorders significantly increased the risk for substance use disorders independently of ADHD status. Mood and anxiety disorders increased the risk for substance use disorders in both the ADHD and comparison subjects, but more demonstrably in the comparison subjects. CONCLUSIONS: Although psychiatric comorbidity increased the risk for psychoactive substance use disorders in adults with ADHD, by itself ADHD was a significant risk factor for substance use disorders. More information is needed to further delineate risk and protective factors mediating the development of substance use disorders in persons with ADHD.

A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder.

OBJECTIVE: Despite the increasing recognition of attention deficit hyperactivity disorder (ADHD) in adults, there is a paucity of controlled pharmacological trials. Recent reports have suggested the potential usefulness of cholinergic agents for ADHD. To this end, the authors completed a controlled study of ABT-418, a novel cholinergic activating agent, for the treatment of adults with ADHD. METHOD: This was a double-blind, placebo-controlled, randomized, crossover trial that compared a transdermal patch of ABT-418 (75 mg/day) to placebo in adults who met DSM-IV criteria for ADHD. There were two 3-week treatment periods separated by 1 week of washout. RESULTS: Of the 32 subjects enrolled in the study (88% were men; mean age = 40 years, SD = 9), 29 completed the study. At the endpoint of each active arm (last observation carried forward), a significantly higher proportion of subjects was considered improved while receiving ABT-418 than while receiving placebo (40% versus 13%). Similarly, at endpoint there was a significantly greater reduction in ADHD symptom checklist scores (28% versus 15%). Symptoms reflective of attention, and subjects with less severe ADHD, responded more robustly to ABT-418. Treatment with ABT-418 was relatively well tolerated; dizziness and nausea were the most frequently reported adverse effects. CONCLUSIONS: The results of this investigation indicate that ABT-418, a nicotinic analog, may be a potentially useful agent for the treatment of ADHD.

Six-week, double-blind, placebo-controlled study of desipramine for adult attention deficit hyperactivity disorder.

OBJECTIVE: Despite the increasing awareness of attention deficit hyperactivity disorder (ADHD) in adults, there are a limited number of controlled pharmacologic studies of this disorder; most of the trials have focused on the psychostimulants. Because the tricyclic anti-depressant desipramine has been found to be effective in treating ADHD in pediatric groups, the authors tested its efficacy in adults with ADHD. METHOD: The authors conducted a randomized, 6-week, placebo-controlled, parallel-design study of desipramine at a target daily dose of 200 mg in 41 adult patients with DSM-III-R ADHD. They used standardized structured psychiatric instruments for diagnosis and, as the dependent variables (outcome), used separate assessments of ADHD, depressive, and anxiety symptoms at baseline and at each biweekly visit. RESULTS: There were highly significant differences in the reduction of ADHD symptoms between adults receiving desipramine and placebo. Within the desipramine-treated group, there were clinically and statistically significant differences between baseline and the week 6 end point for 1) reduction of 12 of 14 symptoms of ADHD and 2) decreases in the broad categories of hyperactivity, impulsivity, and inattentiveness. In contrast, placebo-treated patients showed no differences between baseline and end point for any of the ADHD symptoms assessed. According to strict, predefined criteria for response, 68% of desipramine-treated subjects and no subjects in the placebo group were considered positive responders. Response to desipramine was independent of dose, level of impairment, gender, or lifetime psychiatric comorbidity with anxiety or depressive disorders. CONCLUSIONS: These results, similar to findings in children and adolescents with ADHD, indicate that desipramine is effective in the treatment of ADHD in adults.

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.

Dopamine D4 gene 7-repeat allele and attention deficit hyperactivity disorder.

OBJECTIVE: Family, twin, and adoption studies show attention deficit hyperactivity disorder (ADHD) to have a substantial genetic component, and some studies have reported an association between ADHD and the dopamine D4 (DRD4) gene. METHOD: The authors recruited 27 triads that comprised an ADHD adult, his or her spouse, and their ADHD child. These triads were assessed for ADHD, and their DNA was genotyped for DRD4 alleles. RESULTS: A multiallelic transmission disequilibrium test suggested an association between ADHD and the DRD4 7-repeat allele. Among family members, the number of 7-repeat alleles predicted the diagnosis of ADHD. CONCLUSIONS: Prior reports of an association between ADHD and DRD4 generalize to families recruited through clinically referred ADHD adults. However, because there are some conflicting studies, further work is needed to clarify the role of DRD4 in the etiology of the disorder.

Case study: adverse effects of smoking marijuana while receiving tricyclic antidepressants.

Increasingly, children and adolescents are being treated for underlying psychopathology commonly associated with the psychoactive substance use disorders. Despite this apparent increase in using medication, little is known about the interaction of drugs of abuse with the psychotropic medications. The authors describe four cases of male adolescents aged 15 to 18 years being treated with a tricyclic antidepressant for attention-deficit hyperactivity disorder who manifested transient cognitive changes, delirium, and tachycardia after smoking marijuana.

Clinical characteristics of psychiatrically referred adolescent outpatients with substance use disorder.

OBJECTIVE: There is increasing interest in the developmental relationship of psychopathology and substance use disorders (SUD) in youths. Because the bulk of literature is focused in inpatient or incarcerated youths, inferences and generalizations are limited in outpatient settings. The clinical characteristics of psychiatrically referred outpatients were studied to determine whether differences existed in the nature and severity of comorbid psychiatric disorders when substance abuse was involved. METHOD: All diagnoses were derived from structured psychiatric interviews completed on all youths on intake assessment. Adolescents with an identified SUD (n = 38) were compared with those without SUD (n = 321) on a number of variables including past and current psychopathology, cognitive and school functioning, and overall impairment. RESULTS: Eleven percent of referred outpatients (mean age = 15.9 +/- 1.3 years) met full criteria for a SUD by parental report. Controlling for age, adolescents with SUD had higher risk for mood and disruptive behavioral disorders compared with psychiatric controls. In the majority of cases, the onset of psychopathology preceded the onset of SUD by at least 1 year. The group with SUD also had lower overall functioning and more school dysfunction and psychiatric hospitalizations than their non-SUD peers. CONCLUSIONS: Despite the small number of adolescents with SUD in this sample, these data indicate that SUD is common in outpatient psychiatry referrals. Youths with SUD appear to be at increased risk for more psychopathology and dysfunction in a number of domains.

Case study: nefazodone for juvenile mood disorders.

OBJECTIVE: Despite the increasing recognition of juvenile mood disorders, few medications have been shown to be effective. Nefazodone is a novel antidepressant that remains untested in children. Seven cases are described, including four with bipolar depression, in which nefazodone was used for depression. METHOD: The authors systematically studied the response to nefazodone used naturalistically in seven treatment-refractory and very comorbid children and adolescents (mean age +/- SD, 12.4 + 3.1) with a juvenile mood disorder that was diagnosed clinically and confirmed by structured psychiatric interview. Response to treatment was evaluated retrospectively by an independent rater using the Clinical Global Impression (CGI) of severity and improvement of depression. RESULTS: Children and adolescents received nefazodone for 13 (+/-8) weeks at a mean daily dose of 357 +/- 151 mg (3.4 mg/kg). Fifty-six percent of children and adolescents previously unresponsive to multiple medication trials manifested much to very much improvement as measured by the CGI. Two of four children with bipolar depression responded well to treatment, whereas the other two had mild manic activation. Overall, nefazodone was well tolerated, with adverse effects reported in only three subjects. CONCLUSION: Nefazodone appears to be a well-tolerated compound that may provide a treatment option for juveniles with mood disorders. Further controlled trials are warranted.