Ezra Wegbreit

Visual Attention Modulates Insight Versus Analytic Solving of Verbal Problems.

Behavioral and neuroimaging findings indicate that distinct cognitive and neural processes underlie solving problems with sudden insight. Moreover, people with less focused attention sometimes perform better on tests of insight and creative problem solving. However, it remains unclear whether different states of attention, within individuals, influence the likelihood of solving problems with insight or with analysis. In this experiment, participants (N = 40) performed a baseline block of verbal problems, then performed one of two visual tasks, each emphasizing a distinct aspect of visual attention, followed by a second block of verbal problems to assess change in performance. After participants engaged in a center-focused flanker task requiring relatively focused visual attention, they reported solving more verbal problems with analytic processing. In contrast, after participants engaged in a rapid object identification task requiring attention to broad space and weak associations, they reported solving more verbal problems with insight. These results suggest that general attention mechanisms influence both visual attention task performance and verbal problem solving.

Developmental meta-analyses of the functional neural correlates of bipolar disorder.

IMPORTANCE Bipolar disorder (BD) is a debilitating mental illness associated with high costs to diagnosed individuals and society. Within the past 2 decades, increasing numbers of children and adolescents have been diagnosed as having BD. While functional magnetic resonance imaging (fMRI) studies have begun to investigate the neural mechanisms underlying BD, few have directly compared differences in youths with BD and adults with BD (hereafter BD-youths and BD-adults, respectively). OBJECTIVE To test the hypothesis that BD-youths (<18 years old) would show greater convergence of amygdala hyperactivation and prefrontal cortical hypoactivation vs BD-adults. DATA SOURCES PubMed and PsycINFO databases were searched on July 17, 2013, for original, task-related coordinate-based fMRI articles. STUDY SELECTION In total, 21 pediatric studies, 73 adult studies, and 2 studies containing distinct pediatric and adult groups within the same study met inclusion criteria for our ALE analyses. DATA EXTRACTION AND SYNTHESIS Coordinates of significant between-group differences were extracted from each published study. Recent improvements in GingerALE software were used to perform direct comparisons of pediatric and adult fMRI findings. We conducted activation likelihood estimation (ALE) meta-analyses directly comparing the voxelwise convergence of fMRI findings in BD-youths vs BD-adults, both relative to healthy control (HC) participants. RESULTS Analyses of emotional face recognition fMRI studies showed significantly greater convergence of amygdala hyperactivation among BD-youths than BD-adults. More broadly, analyses of fMRI studies using emotional stimuli showed significantly greater convergence of hyperactivation among BD-youths than BD-adults in the inferior frontal gyrus and precuneus. In contrast, analyses of fMRI studies using nonemotional cognitive tasks and analyses aggregating emotional and nonemotional tasks showed significantly greater convergence of hypoactivation among BD-youths than BD-adults in the anterior cingulate cortex. CONCLUSIONS AND RELEVANCE Our data suggest that amygdala, prefrontal, and visual system hyperactivation is important in the emotional dysfunction present in BD-youths, as well as that anterior cingulate cortex hypoactivation is relevant to the cognitive deficits in BD-youths. Future studies are required to determine if the developmental fMRI differences between BD-youths and BD-adults identified by our ALE meta-analyses are useful as brain-based diagnostic or treatment markers of BD, including either longitudinal neuroimaging studies of BD-youths as they become adults or cross-sectional imaging studies directly comparing BD-youths with BD-adults.

Risperidone and Divalproex Differentially Engage the Fronto-Striato-Temporal Circuitry in Pediatric Mania: A Pharmacological Functional Magnetic Resonance Imaging Study.

OBJECTIVE The current study examined the impact of risperidone and divalproex on affective and working memory circuitry in patients with pediatric bipolar disorder (PBD). METHOD This was a six-week, double-blind, randomized trial of risperidone plus placebo versus divalproex plus placebo for patients with mania (n = 21; 13.6 ± 2.5 years of age). Functional magnetic resonance imaging (fMRI) outcomes were measured using a block design, affective, N-back task with angry, happy, and neutral face stimuli at baseline and at 6-week follow-up. Matched healthy controls (HC; n = 15, 14.5 ± 2.8 years) were also scanned twice. RESULTS In post hoc analyses on the significant interaction in a 3×2×2 analysis of variance (ANOVA) that included patient groups and HC, the risperidone group showed greater activation after treatment in response to the angry face condition in the left subgenual anterior cingulate cortex (ACC) and striatum relative to the divalproex group. The divalproex group showed greater activation relative to the risperidone group in the left inferior frontal gyrus and right middle temporal gyrus. Over the treatment course, the risperidone group showed greater change in activation in the left ventral striatum than the divalproex group, and the divalproex group showed greater activation change in left inferior frontal gyrus and right middle temporal gyrus than the risperidone group. Furthermore, each patient group showed increased activation relative to HC in fronto-striato-temporal regions over time. The happy face condition was potentially less emotionally challenging in this study and did not elicit notable findings. CONCLUSIONS When patients performed a working memory task under emotional duress inherent in the paradigm, divalproex enhanced activation in a fronto-temporal circuit whereas risperidone increased activation in the dopamine (D₂) receptor-rich ventral striatum. Clinical trial registration information-Risperidone and Divalproex Sodium With MRI Assessment in Pediatric Bipolar; http://www.clinicaltrials.gov; NCT00176202.

Amygdala Functional Connectivity Predicts Pharmacotherapy Outcome in Pediatric Bipolar Disorder

The aim of this study was to determine functional connectivity among patients with pediatric bipolar disorder (PBD) who are responders to pharmacotherapy and those who are nonresponders, and learn how they differ from healthy controls (HC) while performing a task that engages affective and cognitive neural systems. PBD participants (n = 34; 13.4 ± 2.3 years) were defined as responders if there was ≥ 50% improvement in Young Mania Rating Scale (YMRS) scores (n = 22) versus nonresponders with < 50% improvement (n = 12) with one of three mood stabilizing medications (divalproex, risperidone, or lamotrigine). HC (n = 14; 14.2 ± 3.1 years) participants also were scanned at baseline and follow-up. During functional magnetic resonance imaging, participants performed a color-matching task in which they had to match the color of positive, negative, or neutral words with colored dots. Independent component analysis was used to identify functionally connected networks across the whole brain, which were subsequently interrogated using region-of-interest analyses to test for group differences. A frontolimbic network was identified that showed impaired functional integration in PBD relative to HC when participants viewed negatively valenced words. PBD medication responders showed greater connectivity of the amygdala into the network before and after treatment compared with nonresponders, with responders showing a pattern more similar to HC than to nonresponders. Regardless of medication type, the degree of amygdala functional connectivity predicted medication response as well as the improvement in YMRS scores across responders and nonresponders. These findings suggest that increased functional integration of the amygdala within the frontolimbic network might be a biomarker of general mood stabilizer medication responsivity in bipolar disorder.

Altered affective, executive and sensorimotor resting state networks in patients with pediatric mania

BACKGROUND The aim of the present study was to map the pathophysiology of resting state functional connectivity accompanying structural and functional abnormalities in children with bipolar disorder. METHODS Children with bipolar disorder and demographically matched healthy controls underwent resting-state functional magnetic resonance imaging. A model-free independent component analysis was performed to identify intrinsically interconnected networks. RESULTS We included 34 children with bipolar disorder and 40 controls in our analysis. Three distinct resting state networks corresponding to affective, executive and sensorimotor functions emerged as being significantly different between the pediatric bipolar disorder (PBD) and control groups. All 3 networks showed hyperconnectivity in the PBD relative to the control group. Specifically, the connectivity of the dorsal anterior cingulate cortex (ACC) differentiated the PBD from the control group in both the affective and the executive networks. Exploratory analysis suggests that greater connectivity of the right amygdala within the affective network is associated with better executive function in children with bipolar disorder, but not in controls. LIMITATIONS Unique clinical characteristics of the study sample allowed us to evaluate the pathophysiology of resting state connectivity at an early state of PBD, which led to the lack of generalizability in terms of comorbid disorders existing in a typical PBD population. CONCLUSION Abnormally engaged resting state affective, executive and sensorimotor networks observed in children with bipolar disorder may reflect a biological context in which abnormal task-based brain activity can occur. Dual engagement of the dorsal ACC in affective and executive networks supports the neuroanatomical interface of these networks, and the amygdalas engagement in moderating executive function illustrates the intricate interplay of these neural operations at rest.

Facial emotion recognition in childhood-onset bipolar I disorder: an evaluation of developmental differences between youths and adults

Bipolar disorder (BD) is a severe mental illness with high healthcare costs and poor outcomes. Increasing numbers of youths are diagnosed with BD, and many adults with BD report that their symptoms started in childhood, suggesting that BD can be a developmental disorder. Studies advancing our understanding of BD have shown alterations in facial emotion recognition both in children and adults with BD compared to healthy comparison (HC) participants, but none have evaluated the development of these deficits. To address this, we examined the effect of age on facial emotion recognition in a sample that included children and adults with confirmed childhood‐onset type‐I BD, with the adults having been diagnosed and followed since childhood by the Course and Outcome in Bipolar Youth study.

Self‐injurious implicit attitudes among adolescent suicide attempters versus those engaged in nonsuicidal self‐injury

BACKGROUND Suicide is among the most important mental health issues affecting adolescents today despite much research on its detection and prevention. Beyond suicide attempts (SAs), clinicians are increasingly confronted with another, potentially related problem: non-suicidal self-injury (NSSI)-defined as the deliberate destruction of body tissue without intent to die. NSSI may increase risk for making an SA by sevenfold, but many studies examining this link have involved youths engaging in both NSSI and SAs. Thus, there is a need to compare homogeneous groups of adolescents engaged in NSSI-only or SA-only, but not both, to advance what is known about each form of self-harm. The self-injurious implicit association task (SI-IAT) is a particularly important computerized behavioral task to study such adolescents because the SI-IAT provides objective behavioral data about problems for which people may lack insight or be motivated to conceal, such as SAs and NSSI. METHODS We evaluated implicit associations with cutting and death/suicide using the computerized SI-IAT in three mutually exclusive groups: (1) adolescents who made an SA but had never engaged in NSSI (n = 47); (2) adolescents who engaged in NSSI but had never made an SA (n = 46); and (3) typically developing control (TDC) adolescents without history of psychiatric problems (n = 43). RESULTS Nonsuicidal self-injury participants had stronger identification with cutting versus no cutting than either SA or TDC participants. Contrary to our hypothesis, NSSI participants had stronger identification with suicide/death versus life than either SA or TDC participants. CONCLUSIONS Strong implicit attitudes towards suicide/death among adolescents with NSSI without a prior SA suggest that clinicians should not dismiss NSSI as not serious. Further work is required to elucidate the mechanism by which youths engaged in NSSI acquire these stronger identifications and make a first-time SA to develop novel treatment and prevention strategies blocking this transformation, ultimately reducing youth suicide.

Cognitive Remediation: Potential Novel Brain-Based Treatment for Bipolar Disorder in Children and Adolescents

Bipolar disorder (BD) is among the most impairing psychiatric disorders affecting children and adolescents, despite our best psychopharmacological and psychotherapeutic treatments. Cognitive remediation, defined as a behavioral intervention designed to improve cognitive functions so as to reduce psychiatric illness, is an emerging brain-based treatment approach that has thus far not been studied in pediatric BD. The present article reviews the basic principles of cognitive remediation, describes what is known about cognitive remediation in psychiatric disorders, and delineates potential brain/behavior alterations implicated in pediatric BD that might be targets for cognitive remediation. Emerging data show that cognitive remediation may be useful in children and adults with schizophrenia, ADHD, and anxiety disorders, and in adults with BD. Potential targets for cognitive remediation in pediatric BD include face processing, response inhibition, frustration, and cognitive flexibility. Further study is warranted to determine if cognitive remediation for these targets, or others, may serve as a novel, brain-based treatment for pediatric BD.

Time course of recovery showing initial prefrontal cortex changes at 16 weeks, extending to subcortical changes by 3 years in pediatric bipolar disorder

OBJECTIVE Activation changes at the interface of affective and cognitive systems are examined over a 3 year period in pediatric bipolar disorder (PBD). METHODS Thirteen participants with PBD and 10 healthy controls (HC) matched on demographics and IQ were scanned at baseline, at 16 weeks, and after 3 years. All patients received pharmacotherapy based on a medication algorithm. A pediatric affective color matching paradigm was used to probe cognitive processing under emotional challenge. RESULTS At baseline, in response to emotional vs. neutral words, patients with PBD showed greater activation than HC in the right dorsal lateral prefrontal cortex (DLPFC) and amygdala, ventral lateral prefrontal cortex (VLPFC), bilateral anterior cingulate cortex (ACC), and ventral striatum. Increased activation in DLPFC in the PBD group normalized by 16 weeks. By 3 years, normalization was observed in VLPFC, ACC, amygdala, and striatum. LIMITATIONS Small sample size renders the present findings preliminary. CONCLUSIONS Greater activation in fronto-striatal and fronto-limbic circuits were observed in unmedicated patients with PBD. Present findings suggest the possibility that DLPFC is most malleable to pharmacological intervention with systematic pharmacotherapy leading to immediate response, which extended to amygdalostriatal and ventral cortical regions at 3 years. The seminal observation from this study is the prolonged length of recovery time in the normalization of subcortical activity along with their interfacing cortical regions. Findings from this proof of concept study need to be replicated in a larger sample.

Reversal-learning deficits in childhood-onset bipolar disorder across the transition from childhood to young adulthood

BACKGROUND Bipolar disorder (BD) is a severe mental illness that can have high costs for youths (<18 years old) and adults. Relative to healthy controls (HC), individuals with BD often show impaired attention, working memory, executive function, and cognitive flexibility (the ability to adapt to changing reward/punishment contingencies). In our study of youths and young adults with BD, we investigated 1) how cognitive flexibility varies developmentally in BD, and 2) whether it is independent of other executive function deficits associated with BD. METHODS We measured errors on a reversal-learning task, as well as spatial working memory and other executive function, among participants with BD (N=75) and HC (N=130), 7-27 years old. Regression analyses focused on the effects of diagnosis on reversal-learning errors, controlling for age, gender, IQ, spatial span, and executive function. Similar analyses examined non-reversal errors to rule out general task impairment. RESULTS Participants with BD, regardless of age, gender, or cognitive ability, showed more errors than HC on the response reversal stages of the cognitive flexibility task. However, participants with BD did not show more errors on non-reversal stages, even when controlling for other variables. LIMITATIONS Study limitations include the cross-sectional, rather than longitudinal, design; inability to measure non-linear age effects; and inclusion of medicated participants and those with psychiatric comorbidity. CONCLUSIONS Individuals with BD show a specific impairment in reversing a previously rewarded response, which persists across the transition from childhood to young adulthood. Tailored interventions targeting this deficit may be effective throughout this developmentally turbulent time.