Cognitive flexibility and performance in children and adolescents with threshold and sub-threshold bipolar disorder.

Greater understanding of cognitive function in children and adolescents with bipolar disorder (BD) is of critical importance to improve our ability to design targeted treatments to help with real-world impairment, including academic performance. We sought to evaluate cognitive performance among children with either BD type I, II, or "not otherwise specified" (NOS) participating in multi-site Course and Outcome of Bipolar Youth study compared to typically developing controls (TDC) without psychopathology. In particular, we sought to test the hypothesis that BD-I and BD-II youths with full threshold episodes of mania or hypomania would have cognitive deficits, including in reversal learning, vs. those BD-NOS participants with sub-threshold episodes and TDCs. N = 175 participants (BD-I = 81, BD-II = 11, BD-NOS = 28, TDC = 55) completed Cambridge Neuropsychological Automated Testing Battery (CANTAB) tasks. A priori analyses of the simple reversal stage of the CANTAB intra-/extra-dimensional shift task showed that aggregated BD-I/II participants required significantly more trials to complete the task than either BD-NOS participants with sub-syndromal manic/hypomanic symptoms or than TDCs. BD participants across sub-types had impairments in sustained attention and information processing for emotionally valenced words. Our results align with prior findings showing that BD-I/II youths with distinct episodes have specific alterations in reversal learning. More broadly, our study suggests that further work is necessary to see the interaction between neurocognitive performance and longitudinal illness course. Additional work is required to identify the neural underpinnings of these differences as targets for potential novel treatments, such as cognitive remediation.

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

OBJECTIVES: 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. METHODS: Using the Diagnostic Analysis of Non-Verbal Accuracy, we compared facial emotion recognition errors among participants with BD (n = 66; ages 7-26 years) and HC participants (n = 87; ages 7-25 years). Complementary analyses investigated errors for child and adult faces. RESULTS: A significant diagnosis-by-age interaction indicated that younger BD participants performed worse than expected relative to HC participants their own age. The deficits occurred both for child and adult faces and were particularly strong for angry child faces, which were most often mistaken as sad. Our results were not influenced by medications, comorbidities/substance use, or mood state/global functioning. CONCLUSIONS: Younger individuals with BD are worse than their peers at this important social skill. This deficit may be an important developmentally salient treatment target - that is, for cognitive remediation to improve BD youths' emotion recognition abilities.

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.

Affective processing bias in youth with primary bipolar disorder or primary attention-deficit/hyperactivity disorder.

High rates of comorbidity and overlapping diagnostic criteria between pediatric bipolar disorder (BD) and attention-deficit/hyperactivity disorder (ADHD) contribute to diagnostic and treatment confusion. To advance what is known about both disorders, we compared effect of emotional stimuli on response control in children with primary BD, primary ADHD and typically developing controls (TDC). Participants included 7-17 year olds with either "narrow-phenotype" pediatric BD (n = 25), ADHD (n = 25) or TDC (n = 25). Groups were matched on participant age and FSIQ. The effect of emotional stimuli on response control was assessed using the Cambridge Neuropsychological Test Automated Battery Affective Go/No-Go task (CANTAB AGN). We found a group by target valence interaction on commission errors [F(2,71) = 5.34, p < 0.01, ƞ p (2) = 0.13] whereby ADHD, but not TDC participants, made more errors on negative than positive words [t(24) = -2.58, p < 0.05, r = 0.47]. In contrast, there was a nonsignificant trend for BD participants to make fewer errors on negative versus positive words compared to ADHD and TDC participants. Between-subjects effects showed that ADHD participants made more errors than TDC, but not BD participants. Our main finding advances what is known about the effect of emotional stimuli on response control in children with ADHD. Our results suggesting a positive affective processing bias in children with ADHD compliment emerging literature show that difficulties with emotional processing and regulation may be core features of ADHD. Further, given the observed pattern of results in children with ADHD compared to BD children, our behavioral results suggest the importance of examining differences in the brain-behavior mechanisms involved in affective processing in children with ADHD compared to BD children.

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.

Behavioral and emotional responses to interpersonal stress: A comparison of adolescents engaged in non-suicidal self-injury to adolescent suicide attempters.

Prominent theoretical models and existing data implicate interpersonal factors in the development and maintenance of suicidal behavior and non-suicidal self-injury (NSSI). However, no known study has yet used computerized behavioral tasks to objectively assess responses to interpersonal conflict/collaboration among teens engaged in NSSI or having made a suicide attempt. The current study, therefore, compared interpersonal functioning indexed by the Prisoner's Dilemma (PD) task among three mutually exclusive groups, adolescents (ages 13-17): engaged in NSSI only without history of a suicide attempt (n=26); who made a suicide attempt without history of NSSI (n=26); and typically developing controls (n=26). Participants also completed the Interpersonal Sensitivity Measure to assess their general sensitivity to/awareness of others' behaviors and feelings. No significant between-group differences were found in PD task performance; however, compared to typically developing control participants and those who had made a suicide attempt, the NSSI group reported significantly more stress during the task. Additionally, NSSI participants rated themselves as more interpersonally sensitive compared to both attempters and typically developing controls. Given the lack of knowledge about whether these groups either differentially activate the same circuitry during stressful interpersonal interactions or instead rely on alternative, compensatory circuits, future work using event-related functional magnetic resonance imaging is warranted.

Circadian Phase Preference in Pediatric Bipolar Disorder.

Pediatric bipolar disorder (BD) rates have notably increased over the past three decades. Given the significant morbidity and mortality associated with BD, efforts are needed to identify factors useful in earlier detection to help address this serious public health concern. Sleep is particularly important to consider given the sequelae of disrupted sleep on normative functioning and that sleep is included in diagnostic criteria for both Major Depressive and Manic Episodes. Here, we examine one component of sleep-i.e., circadian phase preference with the behavioral construct of morningness/eveningness (M/E). In comparing 30 BD and 45 typically developing control (TDC) participants, ages 7-17 years, on the Morningness-Eveningness Scale for Children (MESC), no between-group differences emerged. Similar results were found when comparing three groups (BD-ADHD; BD+ADHD; TDC). Consistent with data available on circadian phase preference in adults with BD, however, we found that BD adolescents, ages 13 years and older, endorsed significantly greater eveningness compared to their TDC peers. While the current findings are limited by reliance on subjective report and the high-rate of comorbid ADHD among the BD group, this finding that BD teens demonstrate an exaggerated shift towards eveningness than would be developmentally expected is important. Future studies should compare the circadian rhythms across the lifespan for individuals diagnosed with BD, as well as identify the point at which BD youth part ways with their healthy peers in terms of phase preference. In addition, given our BD sample was overall euthymic, it may be that M/E is more state vs. trait specific in latency age youth. Further work would benefit from assessing circadian functioning using a combination of rating forms and laboratory-based measures. Improved understanding of sleep in BD may identify behavioral targets for inclusion in prevention and intervention protocols.

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.