Research paperReversal-learning deficits in childhood-onset bipolar disorder across the transition from childhood to young adulthood
Introduction
Bipolar disorder (BD) is a highly impairing psychiatric illness, with health care costs estimated to be twice those of depression (Keck et al., 2008, Kleinman et al., 2003) and a prevalence of 1–4% in the general population (Merikangas et al., 2007, Merikangas et al., 2012). BD often leads to serious health and psychosocial problems, and tragically even suicide (Holma et al., 2014, Keck et al., 2008, Kleinman et al., 2003). While many assume BD solely affects adults, ample research especially during the past two decades demonstrates that BD may also affect children and adolescents (hereafter “youths” age <18 years old). As in adults, BD in youths can be a devastating illness associated with high health care costs, poor psychosocial outcomes, and suicide (Dusetzina et al., 2012, Hauser et al., 2013, Leverich et al., 2007, Romero et al., 2009). Increasing numbers of youths are being diagnosed with and treated for BD – a 40% increase in one study - as evidenced by both inpatient and outpatient clinical data from the US and abroad (Blader and Carlson, 2007, Holtmann et al., 2010, Moreno et al., 2007). Furthermore, while BD symptoms may start in childhood (Leboyer et al., 2005), many patients are not formally diagnosed with BD until adulthood, potentially creating substantial delays in receiving BD-specific treatments (Leverich et al., 2007). Altogether, a critical need exists for more studies to include both children and young adults with BD so as to examine how the phenomenology and pathophysiology of BD change across the lifespan.
In studies involving either youths (Dickstein et al., 2004, Joseph et al., 2008, Kyte et al., 2006, Pavuluri et al., 2006a, Pavuluri et al., 2006b; Pavuluri et al., 2006a, Pavuluri et al., 2006b) or adults with BD (Badcock et al., 2005, Green, 2006, Jabben et al., 2010, Roiser et al., 2009, Sweeney et al., 2000), but not both groups in the same study, BD is associated with cognitive deficits, including impaired attention, working memory, executive function, and response inhibition—all compared to healthy controls (HC) without psychopathology. Although several functional magnetic resonance imaging (fMRI) studies have compared youths and adults with BD on facial emotion recognition tasks (e.g., Brotman et al., 2013), fewer studies have directly compared cognitive deficits between youths and adults with BD (Wegbreit et al., 2014). Two such fMRI studies involving response inhibition tasks found that youths with BD showed more neural alterations than adults with BD in the inferior frontal gyrus and the anterior cingulate cortex, which are involved in cognitive control (Weathers et al., 2013, Weathers et al., 2012). Moreover, in an fMRI meta-analysis, youths with BD showed more consistently decreased anterior cingulate activation during cognitive tasks than adults with BD (Wegbreit et al., 2014). These cognitive problems are important to study because many are associated with reduced psychosocial functioning and do not remit during euthymia (Andreou and Bozikas, 2013, Buoli et al., 2014, Mora et al., 2013, Pavuluri et al., 2006a, Pavuluri et al., 2009, Peters et al., 2014; Pavuluri et al., 2006a, Pavuluri et al., 2009, Peters et al., 2014). Better knowledge of their pathophysiology could provide a cost-effective way to improve the lives of individuals with BD by spurring the development of novel pharmacological agents (Miskowiak et al., 2014) and cognitive remediation treatments (Dickstein et al., 2015b).
Another cognitive construct that has been investigated in separate studies of BD adults or BD youths is cognitive flexibility, defined as adapting to changes in rewards and punishments (Cools et al., 2002, Cools et al., 2004). Reversal-learning tasks are one laboratory measure of cognitive flexibility, whereby participants use trial-and-error learning to determine which of two objects is rewarded vs. punished. Then, without warning, the stimulus/reward association reverses, so that the previously rewarded stimulus is now punished, and vice versa. During reversal learning, youths with BD make more errors than HC youths (Dickstein et al., 2010a, Dickstein et al., 2007, Dickstein et al., 2004, Gorrindo et al., 2005) and show specific alterations in regions involved in cognitive control, including ventral prefrontal cortex (vPFC) and ventral striatum (VS) (Adleman et al., 2011, Dickstein et al., 2010b; Dickstein et al., 2010b). Adults with BD are less consistent, as some studies revealed behavioral deficits in reversal learning vs. adult HCs and associated vPFC and VS alterations (Clark et al., 2001, Clark et al., 2002, Kozicky et al., 2013, Linke et al., 2013, Linke et al., 2012, McKirdy et al., 2009), but others have not (Roiser et al., 2009, Rubinsztein et al., 2000, Sweeney et al., 2000). To the best of our knowledge, no study has examined altered response reversal in BD using a developmental framework including both youths and adults with BD.
Consequently, we examine response reversal in participants with childhood-onset BD, including both young adults (those ≥18) and youths (those <18). Specifically, we enrolled adults who had been followed for BD since childhood by the Brown University site of the Course and Outcome of Bipolar Youth (COBY) study to ensure that retrospective recall bias did not affect these participants’ BD diagnosis (Birmaher et al., 2009, Leboyer et al., 2005). This strategy also eliminates another potential confound because all participants had early-onset BD, rather than comparing youths with childhood-onset BD to adults with adult-onset BD. We employed age as a continuous variable to search for specific diagnosis-by-age interactions, as our prior work suggests that younger people with BD show delayed development in their facial emotion recognition ability (Wegbreit et al., 2015). Thus, we hypothesized that younger participants with BD would also show worse reversal-learning performance than expected for their age relative to older participants with BD (Jarcho et al., 2012, Wegbreit et al., 2015). Moreover, we conducted additional analyses to determine how cognitive flexibility deficits relate to broader deficits in executive function, given that spatial span predicts planning ability in participants with BD (Badcock et al., 2005). These extended analyses investigated whether cognitive flexibility deficits in BD are independent of other executive functioning deficits, including mental storage capacity (spatial span) and planning ability (tested by the Stockings of Cambridge task).
Section snippets
Participants
All participants were enrolled in Institutional Review Board-approved research studies conducted at Bradley Hospital and Brown University. After written informed consent and assent were obtained, participants’ psychiatric symptoms and history were assessed using the Child Schedule for Affective Disorders and Schizophrenia, Present and Lifetime Version (K-SADS-PL) (Kaufman et al., 1997) administered to participants under 18 years old and their parents separately, or the Structured Clinical
Demographics
Overall, the BD and HC groups as a whole showed a significant difference in FSIQ but not age. For categorical variables, BD and HC groups showed a significantly different distribution of White vs. non-White participants, but their gender distribution did not significantly differ (Table 1). To compare with prior literature that splits youths and adults into groups, we tested for age-by-diagnosis interactions and found no significant effects (Table 2). We also report clinical variables, such as
Discussion
Our study is the first to take a developmental approach to investigate impaired cognitive flexibility in youths and young adults with BD. Our primary findings were: (1) participants with BD made significantly more errors than HC on reversal stages, but not on non-reversal stages; (2) participants with BD showed reduced executive functioning and working memory capacity vs. HC; (3) however, we found a specific reversal-learning deficit for participants with BD even when controlling for working
Conclusions
People with childhood-onset BD exhibit a specific deficit in reversal learning, which generalizes across genders and across the developmental transition from late childhood to early adulthood. Further research can build on these findings in two ways. Longitudinal studies following participants with childhood-onset BD could examine the course and functional significance of reversal-learning deficits. Furthermore, targeted cognitive remediation interventions could attempt to ameliorate this
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