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

Dickstein, Daniel P.; Axelson, David; Weissman, Alexandra B.; Yen, Shirley; Hunt, Jeffrey; Goldstein, Benjamin I.; Goldstein, Tina R.; Liao, Fangzi; Gill, Mary Kay; Hower, Heather; Frazier, Thomas; Diler, Rasim Somer; Youngstrom, Eric A.; Fristad, Mary A.; Arnold, L. Eugene; Findling, Robert L.; Horwitz, Sarah M.; Kowatch, Robert A.; Ryan, Neal D.; Strober, Michael; Birmaher, Boris; Keller, Martin B.

doi:10.1007/s00787-015-0769-2

Cited by 26 publications

(9 citation statements)

References 51 publications

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“…Given the robust reductions of circHomer1a in the OFC and the relevance of this brain region for cognitive flexibility, our data showing specific behavioral deficits in reversal learning following in vivo circHomer1a knockdown suggest the possibility that dysregulation of this cir-cRNA in the brain of subjects with BD or SCZ could be associated with some of the cognitive disturbances observed in these psychiatric disorders. Interestingly, multiple studies suggest that alterations in reversal learning have also been observed in patients with BD and SCZ [76][77][78][79][80]. Moreover, the observed reductions of circHomer1a in both the OFC and DLPFC of patients with SCZ suggest that its alterations in SCZ could be more widespread than in BD, which is in accordance with previous reports on miRNA dysregulation in multiple PFC regions in SCZ [11].…”

Section: Discussionsupporting

confidence: 89%

A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

et al. 2020

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Although circular RNAs (circRNAs) are enriched in the mammalian brain, very little is known about their potential involvement in brain function and psychiatric disease. Here, we show that circHomer1a, a neuronal-enriched circRNA abundantly expressed in the frontal cortex, derived from Homer protein homolog 1 (HOMER1), is significantly reduced in both the prefrontal cortex (PFC) and induced pluripotent stem cell-derived neuronal cultures from patients with schizophrenia (SCZ) and bipolar disorder (BD). Moreover, alterations in circHomer1a were positively associated with the age of onset of SCZ in both the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). No correlations between the age of onset of SCZ and linear HOMER1 mRNA were observed, whose expression was mostly unaltered in BD and SCZ postmortem brain. Using in vivo circRNA-specific knockdown of circHomer1a in mouse PFC, we show that it modulates the expression of numerous alternative mRNA transcripts from genes involved in synaptic plasticity and psychiatric disease. Intriguingly, in vivo circHomer1a knockdown in mouse OFC resulted in specific deficits in OFCmediated cognitive flexibility. Lastly, we demonstrate that the neuronal RNA-binding protein HuD binds to circHomer1a and can influence its synaptic expression in the frontal cortex. Collectively, our data uncover a novel psychiatric diseaseassociated circRNA that regulates synaptic gene expression and cognitive flexibility.

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Section: Discussionsupporting

confidence: 89%

A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

et al. 2020

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“…Thus, while we had a great deal of information about our participants, including age of BD illness onset and assessment for psychopathology, mood, and functioning at the time of CANTAB testing, we did not have prospective information for the child BD participants about number and duration of mood episodes prior to testing. Given that some, but not all studies suggest that clinical course influences cognitive performance, further work is needed using longitudinal studies assessing both psychopathology and cognitive performance (Cardoso et al, 2015; Dickstein et al, 2015a). Our lack of age effects or age-diagnosis interactions could also stem from cohort differences between our younger participants with BD and our older participants with BD.…”

Section: Discussionmentioning

confidence: 99%

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

Wegbreit

Cushman

Weissman

et al. 2016

Journal of Affective Disorders

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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 nonreversal 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.

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“…This poor attentional control might alter the ability to direct attention away from distracting stimuli (Maalouf et al 2010), particularly when these are emotionally relevant (Mullin et al 2012). Accordingly, recent studies reported that BD patients show deficits in cognitive flexibility in parallel with impairments in sustained attention and information processing for emotionally valenced words (Dickstein et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Rumination related activity in brain networks mediating attentional switching in euthymic bipolar patients

Apazoglou

Küng

Cordera

et al. 2019

Int J Bipolar Disord

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IntroductionMood disorder patients have a tendency to be more internally oriented, with difficulties in switching attentional focus, which might result in the generation of negative thoughts, such as rumination. The present study explored self-referential neural activity correlating with rumination tendency and attentional switching capacity in bipolar disorder.MethodsTwenty euthymic bipolar patients and twenty matched healthy controls underwent a novel introspection task of switching between internally and externally focused attention during a word processing task, while their brain activity was assessed using functional MRI.ResultsDuring internal focus, higher activity in self-related regions (mPFC, PCC) was found in euthymic bipolar patients as compared to controls, verifying the hypothesis of exaggerated recruitment of self-referential processes in bipolar subjects. Switching from internal to external focus revealed higher parahippocampal activity in patients as compared to controls, additionally more pronounced when switching away from negative as compared to positive self-referential information. Furthermore, rumination traits correlated with activity in PCC, subgenual and pregenual ACC, and bilateral anterior insula during repetition of internal focus, specifically when evaluating negative words. Finally, we used ACC subregions that correlated with tendency to ruminate as seeds for a whole brain connectivity analysis. Patients showed stronger connectivity between sgACC (seed), pgACC, dPFC, and anterior insula during internal focus, whereas pgACC (seed) was more strongly connected to parahippocampal gyrus when switching from internal to external focus.ConclusionsThese findings reveal an overactive rumination-related network whose activity is enhanced by negative information in euthymic bipolar patients, which could possibly contribute to impaired switching of thoughts away from internal attention.Electronic supplementary materialThe online version of this article (10.1186/s40345-018-0137-5) contains supplementary material, which is available to authorized users.

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

Cited by 26 publications

References 51 publications

A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

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

Rumination related activity in brain networks mediating attentional switching in euthymic bipolar patients

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