Emotional modulation of response inhibition in stable patients with bipolar I disorder: a comparison with healthy and schizophrenia subjects.

OBJECTIVES: Bipolar disorder (BD) has been associated with impairment in affective processing during depressive and manic states; however, there are limited data as to whether this population exhibits such difficulty during stable periods. We examined the pattern of affective processing in stable BD patients and compared their profile to that of healthy controls (HC) and patients diagnosed with schizophrenia (SZ). METHODS: A total of 336 subjects were administered an Affective Go/No-go test to evaluate target detection of negatively valenced, positively valenced, and neutral stimuli. Accuracy and response bias served as dependent variables in a series of multivariate analyses of covariance to test for group differences. RESULTS: The BD group relative to the HC group exhibited response biases toward negatively valenced information (p<0.01). Deficits were also evident in discrimination of and accurate responses to positively valenced information in the BD group versus the HC group (p<0.05). In contrast to the controls, the SZ group performed poorly on all task components and was less accurate across all conditions regardless of affective valence (p<0.01). Patients with SZ evidenced reverse biases for positive information, as they were less likely to respond to positive words (p<0.05) despite comparable response bias on neutral and negative conditions. CONCLUSIONS: Affective processing impairment evident in BD is a feature of the disorder that is present even during stable periods. Prior studies comparing BD with SZ have highlighted clear quantitative but inconsistent qualitative differences in cognitive functioning. Our data suggest that a response bias toward negative stimuli may be a critical and relatively specific feature of BD.

Mother-child dyadic synchrony is associated with better functioning in hyperactive/inattentive preschool children.

BACKGROUND: Hyperactive/inattentive (HI) behaviors are common in preschoolers, but they result in functional impairment and attention deficit/hyperactivity disorder (ADHD) diagnoses in only some children. We examined whether the quality of mother-child interaction accounts for variance in level of functioning among preschool children with elevated ADHD symptoms. METHOD: Parent and teacher ADHD-RS ratings were used to assess 126 HI preschoolers, and clinician Children's Global Assessment Scale (CGAS) ratings were used to quantify level of functioning. Mother-child interactions during a 5-minute free-play and a 5-minute structured task were coded for child, parent and dyadic behaviors. RESULTS: Partial correlations, controlling for symptom severity and IQ, revealed child and dyad factors that were related to children's functioning. Regression analyses revealed that low dyadic synchrony accounted for additional unique variance in children's functioning, above and beyond the influence of symptom severity and IQ. CONCLUSIONS: Dyadic synchrony between mother and child plays a role in the functioning of preschool children displaying elevated symptoms of hyperactivity/inattention, and may represent a potential area for intervention that is not generally addressed in most parent management training programs.

Affective modulation of target detection in deficit and non-deficit schizophrenia.

Emotional deficits are an integral feature of schizophrenia (SZ), but our understanding of these deficits is limited. In the present study, we examined whether the severity of emotional deficits reflects difficulty in the cognitive processing of affectively valenced stimuli. Healthy controls (HC; N = 170) and stable outpatients with SZ (N = 245), characterized as either deficit syndrome (DS; N = 62) or non-deficit syndrome (NDS; N = 183), completed an Affective Go/NoGo task requiring discrimination of positively, negatively or neutrally valenced words. Accuracy (d') and response bias (c) were calculated for each of the three conditions, and a series of ANOVAs were carried out to examine group differences. Examination of accuracy revealed significant main effects of group and valence and a significant valence × group interaction, indicating that while affective valence impacted accuracy for the HC and NDS groups, the DS group maintained the same low level of accuracy across all levels of affective valence. Examination of response bias also revealed significant main effects of group and valence and a significant valence × group interaction. Specifically, within the HC and NDS groups, response bias did not differ between negatively and positively valenced words while response bias in the DS group was lowest for neutral, higher for negatively valenced and higher still for positively valenced words. These results suggest that emotional deficits in DS may be directly related to deficits in processing affective information. Moreover, although this deficit is observed across both positively and negatively valenced stimuli, it is most pronounced for positively valenced material.

White Matter Abnormalities Associated With Subsyndromal Psychotic-Like Symptoms Predict Later Social Competence in Children and Adolescents.

INTRODUCTION: Recent data suggest that healthy children and adolescents who report psychotic-like experiences (PLEs) evidence abnormalities in white matter (WM). To date, no study has examined whether WM abnormalities associated with PLEs are predictive of outcome at a later time-point. The present study examined whether abnormalities in WM associated with PLEs in children and adolescents at a baseline assessment were predictive of social functioning at a 12-month follow-up. SUBJECTS AND METHODS: Healthy children and adolescents aged 8-18 years (N = 56) were recruited from the community and received a diffusion tensor imaging exam and a clinical exam at baseline. Voxel-wise statistical analysis of fractional anisotropy (FA), using Tract-Based Spatial Statistics, and probabilistic tractography were used to identify WM abnormalities associated with PLEs at baseline. These abnormalities were then examined for association to social problems and social competence in 28 participants at 12-month follow-up. RESULTS: Lower FA in regions proximal to the superior longitudinal fasciculus (SLF) and corticospinal tract bilaterally as well as in the left inferior fronto-occipital fasciculus and inferior longitudinal fasciculus were associated with higher levels of PLEs at baseline. Moreover, baseline FA in the SLF, but not baseline severity of PLEs, was significantly predictive of social competence at a 12-month follow-up. In contrast, baseline severity of PLEs, but not baseline FA in the SLF, predicted social problems at 12-month follow-up. DISCUSSION: These findings suggest that alterations in WM, which are associated with symptoms of psychosis well below the threshold of clinical significance, may have significant ramifications for later social development.

The interplay among temperament, neuropsychological abilities, and global functioning in young hyperactive/inattentive children.

Cognition and emotion have been shown to interact and influence psychological functioning. However, to date these interactions have only been examined cross-sectionally among inattentive and/or hyperactive/impulsive children. This study investigated the moderating effects of neuropsychological functioning at age 3-4 years on the relation between negative emotionality at age 3-4 years and global functioning 1 year later, at age 4-5 years. Hyperactive/inattentive (H/I; n = 114) preschoolers entered the study (BL: baseline) and were seen again 1 year later (F1). Children's BL scores on a neuropsychological test (NEPSY) and their temperament as rated by parents (Child Behavior Questionnaire) and teachers (Temperament Assessment Battery for Children-Revised) were obtained, as were clinicians' ratings of their global functioning (Children's Global Assessment Scale) at F1. Hierarchical linear regression analyses revealed that BL temperament variables accounted for significant variance in F1 Global Functioning. Significant interactions indicated that higher Verbal Executive abilities were associated with better child functioning when parent-rated Effortful Control was high, but not when Effortful Control was low. Additionally, high levels of Nonverbal Executive skills were associated with higher child global functioning when both parent- and teacher-rated negative affect was low, but not when negative affect was high.

Dopaminergic influences on emotional decision making in euthymic bipolar patients.

We recently reported that the D2/D3 agonist pramipexole may have pro-cognitive effects in euthymic patients with bipolar disorder (BPD); however, the emergence of impulse-control disorders has been documented in Parkinson's disease (PD) after pramipexole treatment. Performance on reward-based tasks is altered in healthy subjects after a single dose of pramipexole, but its potential to induce abnormalities in BPD patients is unknown. We assessed reward-dependent decision making in euthymic BPD patients pre- and post 8 weeks of treatment with pramipexole or placebo by using the Iowa Gambling Task (IGT). The IGT requires subjects to choose among four card decks (two risky and two conservative) and is designed to promote learning to make advantageous (conservative) choices over time. Thirty-four BPD patients completed both assessments (18 placebo and 16 pramipexole). Baseline performance did not differ by treatment group (F=0.63; p=0.64); however, at week 8, BPD patients on pramipexole demonstrated a significantly greater tendency to make increasingly high-risk, high-reward choices across the five blocks, whereas the placebo group's pattern was similar to that reported in healthy individuals (treatment × time × block interaction, p<0.05). Analyses of choice strategy using the expectancy valence model revealed that after 8 weeks on pramipexole, BPD patients attended more readily to feedback related to gains than to losses, which could explain the impaired learning. There were no significant changes in mood symptoms over the 8 weeks, and no increased propensity toward manic-like behaviors were reported. Our results suggest that the enhancement of dopaminergic activity influences risk-associated decision-making performance in euthymic BPD. The clinical implications remain unknown.

MATRICS cognitive consensus battery (MCCB) performance in children, adolescents, and young adults.

BACKGROUND: Neurodevelopmental models of schizophrenia suggest that cognitive deficits may be observed during childhood and adolescence, long before the onset of psychotic symptoms. Elucidating the trajectory of normal cognitive development during childhood and adolescence may therefore provide a basis for identifying specific abnormalities related to the development of schizophrenia. The MATRICS Consensus Cognitive Battery (MCCB), which was designed for use in clinical trials targeting cognitive deficits most common in schizophrenia, may provide a mechanism to understand this trajectory. To date, however, there is no performance data for the MCCB in healthy children and adolescents. The present study sought to establish performance data for the MCCB in healthy children, adolescents, and young adults. METHODS: The MCCB was administered to a community sample of 190 healthy subjects between the ages of 8 and 23years. All MCCB domain scores were converted to T-scores using sample means and standard deviations and were compared for significant performance differences between sex and age strata. RESULTS: Analyses revealed age effects following quadratic trends in all MCCB domains, which is consistent with research showing a leveling off of childhood cognitive improvement upon approaching late adolescence. Sex effects after controlling for age only presented for one MCCB domain, with males exhibiting well-known spatial reasoning advantages. CONCLUSIONS: Utilizing this performance data may aid future research seeking to elucidate specific deficits that may be predictive of later development of SZ.

ADHD Preschoolers with and without ODD: do they act differently depending on degree of task engagement/reward?

OBJECTIVE: To examine the impact of reinforcement on reaction time (RT) and RT variability (RT standard deviation [RTSD]) in preschoolers with ADHD with and without oppositional defiant disorder (ODD), and a typically developing (TD) comparison group. METHOD: Participants were administered a computerized task consisting of two conditions: simple RT (SRT) and reinforced SRT (SRTr). Data were analyzed using two-way (Group × Condition) mixed ANOVAs and followed-up using pairwise comparisons. RESULTS: RTs were significantly shorter and less variable during the SRTr than the SRT condition. A significant Group x Condition interaction was observed for RTSD (F= 3.38, p < .05); post hoc analyses indicated that the RTSD of the ADHD + ODD group was significantly more variable than that of the TD group during the SRT condition (F = 4.81, p < .05). However, their RTSD was statistically indistinguishable from the other groups during the SRTr condition. CONCLUSION: Preschoolers who are oppositional/defiant and hyperactive are the most responsive to feedback/reward.

Emotional bias in unaffected siblings of patients with bipolar I disorder.

BACKGROUND: Bipolar disorder (BPD) research has identified a number of neurocognitive deficits as potential vulnerability markers; however, very few studies have focused on patterns of performance on affective processing tasks (e.g. affective Go/No-Go tasks) which may be more closely tied to the pathophysiology of the illness. We previously reported that stable BPD patients demonstrate a response bias toward negative affective stimuli as compared with healthy controls and schizophrenia patients. The goal of the current study was to expand upon these prior findings to investigate these patterns in the unaffected siblings of BPD patients. METHODS: An affective Go/No-Go test was used to evaluate inhibitory response to negatively-valenced, positively-valenced, and neutral stimuli in 20 unaffected siblings of bipolar I patients versus 20 healthy controls. Accuracy (d') and response bias (beta) served as dependent variables in a series of repeated measures ANCOVAs. RESULTS: We found a non-significant main effect for group when comparing accuracy performance (d') on the affective Go/No-Go of unaffected siblings versus healthy controls. However, very similar to the pattern that we previously reported in stable BPD patients, unaffected siblings showed a response bias (beta) toward negatively-valenced stimuli versus healthy controls [F=3.81; p=0.03]. LIMITATIONS: Small sample size. CONCLUSIONS: The current results extend our recent work which suggested that stable bipolar patients attend more readily to negative target stimuli than do schizophrenic or healthy subjects. These data, indicating that unaffected siblings also demonstrate an affective processing bias, implicate this task as a potential endophenotype in BPD.

Pharmacogenetic approaches to cognitive enhancement in schizophrenia.

Research in the area of pharmacogenetics in psychiatry is aimed at identifying clinically relevant genetic variations that can predict treatment response. Ultimately, the goal is to individualize treatment in order to optimize outcome in disorders in which incomplete treatment response is common. Positive symptoms in patients with schizophrenia appear to be the most amenable to the currently available agents; however, negative symptoms and cognitive deficits frequently persist even when frank psychosis is well controlled. Given the relationship between these persistent traits and functional disability in schizophrenia, efforts are under way to directly target cognitive impairment and negative symptoms pharmacologically in order to improve quality of life. To date, most pharmacogenetic studies of schizophrenia have been focused on predicting clinical efficacy and side effects. In this review, we discuss the potential use of cognition as a primary outcome measure of interest in future pharmacogenetic trials of schizophrenia.

The MATRICS consensus cognitive battery in patients with bipolar I disorder.

The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative was devised to identify a neurocognitive battery to be used in clinical trials targeting cognition in schizophrenia, a process, which resulted in the MATRICS Consensus Cognitive Battery (MCCB). The MCCB has been selected by the United States Food and Drug Administration to be used as the primary outcome measure in registry trials for cognitive agents in schizophrenia. Given the clinical and cognitive overlap between schizophrenia and bipolar disorder (BPD), it is likely that any compound shown to have cognitive benefits in schizophrenia will subsequently be tested in BPD. Unlike the MCCB for schizophrenia, there remains no consensus regarding outcome measures if cognitive trials were to be undertaken in BPD. The utility of the MCCB in BPD has not yet been systematically investigated. We administered the MCCB to 80 bipolar I patients; 37 were strictly euthymic and 43 were symptomatic. We compared their performance with a demographically matched healthy sample (n=148) on seven MCCB domains, and the composite. BPD patients were statistically significantly impaired on five of seven MCCB domains at levels consistent with meta-analytic studies of cognition in BPD. In contrast, patients' performance was less impaired on the Reasoning and Problem-solving and Social Cognition domains, differences that did not survive statistical correction for multiple testing. Symptomatic status only modestly influenced performance. These data suggest that the MCCB, devised for use in schizophrenia, may also represent a useful outcome measure in cognitive trials for BPD. Additional studies should address important psychometric features such as repeatability and potential practice and/or ceiling effects.