We tested two hypotheses in our present study, the first to evaluate the neural basis of reversal learning deficits in pediatric BD. Specifically, we predicted BD youths would demonstrate dysfunction in regions associated with processing response conflict, implementing alternative responses, and controlling attention (i.e., dmFC, iFC, lsFC, parietal cortex, and caudate), and/or that BD youths would show dysfunction in regions of mOFC associated with reinforcement processing. Consistent with the former hypothesis, we found that pediatric BD participants had significantly greater neural activity than controls in the dmFC, lsFC, and parietal cortex during the reversal phase, particularly in response to punished reversal errors. We did not find support for the second hypothesis, as we observed no between-group differences in mOFC activation for which our fronto-parietal findings would be compensating. Nevertheless, we can not make strong claims in this regard because the study does not have sufficient statistical power to rule out a type II error if anything less than a large effect size occurs within this region. Moreover, it should be noted that BD youths showed less deactivation than did controls in other regions previously seen to show deactivation in the context of punishments during reversal learning tasks, including the posterior cingulate cortex and precuneus (7
). Given that our analysis only included euthymic BD youths, these between-group differences are unlikely to be artifacts of mood state.
Our work is the first to begin to elucidate the neural underpinnings of cognitive flexibility using a reversal learning task in pediatric BD. Compared to controls, BD youths had greater activation during the reversal phase, particularly during reversal errors, in the dmFC, iFC, lsFC, and parietal cortex. It has been hypothesized that the dmFC is engaged during the response conflict following punished reversal errors, and that this region recruits regions implicated in top-down attentional control and object/response selection to orchestrate a change in response on the subsequent trial (18
). We found increased activity in BD versus controls during punished reversal errors in the dmFC, lateral regions of the superior and middle frontal cortex, and the parietal cortex. This finding suggests two possibilities. First, since task performance did not differ between groups, this increased activity may reflect inefficient recruitment of these regions to achieve satisfactory task performance. Second, this increased activity may reflect compensatory activity in response to dysfunction elsewhere.
The available literature provides more support for the first possibility. In previous work with euthymic adults with BD, there have been reports of enhanced activity within these regions during successful performance on other tasks that engage psychological processes involved in reversal learning. Thus, for example, euthymic BD adults show greater iFC activation than controls during an emotional go/no-go task when inhibiting emotional versus neutral stimuli (62
). Euthymic BD adults also show greater neural activation than controls in the parietal cortex during a two-back working memory task (63
). In addition, euthymic BD adults show greater PFC activation than controls during an affective face-matching task (64
). Moreover, pediatric BD participants demonstrated increased lsFC activity when successfully performing change trials on a motor control task (52
). In contrast, we did not find support for the second possibility (compensation) because we did not detect neural alterations in other areas, such as the mOFC, for which these fronto-parietal alterations would be compensating. However, caution is urged so as not to commit a type II error by overinterpreting a negative finding, and thus the current data cannot fully distinguish between these two possibilities.
In addition to showing increased activity versus controls in dmPFC and parietal regions during punished reversal errors, on these trials BD youths also showed less deactivation than controls in the posterior cingulate cortex and precuneus. Previous work is consistent with ours in finding that, during punished reversal errors, healthy individuals show decreased activation to punishment versus reward within these regions (7
). Decreased neural responding following punishment has been assumed to relate to recoding of the reinforcement value associated the response (7
). Thus, our data suggest the possibility that a reduced ability to recode reinforcement values requires a compensatory increased recruitment of the dmFC, lsFC, and parietal cortex in order to achieve successful response change.
Importantly, we did not find between-group differences in the mOFC. It is possible that this represents a type II error, and that OFC dysfunction would be detected with either a larger sample of BD and controls, or a more homogeneous sample of BD youths. For example, gender effects have been demonstrated in BD youths in several brain regions, including the OFC (40
). While our study is underpowered to examine such possibilities, another possibility is that reversal learning impairments do not involve the OFC in pediatric BD. Support for the latter possibility comes from another study using this PRR paradigm, which found that both typically developing control children and those with ADHD had the expected decrease in BOLD signal in the OFC to reversal errors, but those with psychopathic tendencies did not (7
). That study, by Finger et al. (7
), involved three groups of 14 children, none of whose data are included in our present study. Additional support comes from a recent study of BD adults (66
) that did not find differences in OFC volume or that of its subregions (including the mOFC) in BD adults compared to controls, although differences were found between depressed and euthymic BD adults. Thus, it is possible that there are diagnosis-specific effects on the brain/behavior interactions underlying reversal learning in child psychiatric disorders. Our future work is geared toward addressing both possibilities.
Although highly speculative, there are several potential clinical implications of our present study. Our data potentially suggest inefficient functioning of a series of regions implicated in attentional control and response selection. In turn, this suggests the possibility that BD youths may have difficulty maximally utilizing psychotherapies relying on such cognitive capacities. However, studies have demonstrated that when such therapies are modified to address BD-specific deficits in cognitive flexibility—e.g., when they include skills training to address impaired problem solving and affect regulation—they have great promise in the treatment of BD. Such therapies include cognitive behavioral therapy [studied in BD adults and children (67
)], family-focused therapy [studied in BD children (68
)], and interpersonal social rhythm therapy [studied in BD adults (69
)]. In this context, it is also interesting to consider whether the brain/behavior interactions underlying cognitive flexibility and reversal learning impairments in pediatric BD may respond to training, such as the use of specialized computer games for ‘cognitive remediation’ (70
There are several caveats and limitations of our study. First, while we previously found impaired performance on reversal learning paradigms in children with BD (15
), we observed no significant group differences in behavior here. This contrast with previous behavioral studies likely reflects task differences between the current fMRI study and previous behavioral work. Importantly, the failure to find between-group behavioral differences eliminates the possibility that our fMRI results are epiphenomena of, or are confounded by, group differences in task performance. Along these lines, it is common for fMRI studies in psychiatric patients to find between-group differences in neural activity without between-group behavioral differences; an example is the recent study in children with psychopathy versus controls that used the same reversal learning paradigm as here (7
). Indeed, some have argued that fMRI is more sensitive than behavior in detecting important between-group differences (72
). On the other hand, others suggest that the absence of between-group behavioral differences complicates attempts to link the observed differences in brain activity to symptoms (73
). Although from this perspective, the lack of between-group behavioral differences might call into question whether reversal tasks engage neural circuitry relevant to the pathophysiology of BD, ample evidence, including our own work in pediatric BD and that of others in BD adults, documents that reversal learning and cognitive flexibility deficits are present in BD (74
Other potential limitations of our study include potential heterogeneity in the BD sample, including that due to psychiatric comorbidities, psychotropic medications, BD subtypes, and possible subsyndromal mood symptoms, as well as the wide age range of our participants. All of our BD youth had one or more co-occurring psychiatric disorders, most commonly ADHD or anxiety disorders. This is consistent with prior research showing that both pediatric and adult BD are characterized by high rates of comorbidity (77
). However, our exploratory secondary analyses showed that our primary findings between patients and controls remained significant even when restricting the BD sample to those without ADHD (n = 6) or to those without an anxiety disorder (n = 10), suggesting that our results are not confounded by comorbid ADHD or anxiety. A study of adolescents with ADHD found no atypical neural response associated with acquisition correct versus reversal incorrect responses when performing this same reversal learning task (7
). Hence, our results here add to an emerging body of literature suggesting that ADHD presenting in the context of BD may be a phenocopy of ADHD presenting alone (14
). Nonetheless, further work is necessary to directly evaluate the specificity of brain/behavior interactions underlying reversal learning in pediatric BD. For example, such work might compare directly youth with BD to those with either primary ADHD or primary anxiety disorders, as well as comparing BD youth with versus without comorbid ADHD and BD youth with versus without comorbid anxiety (82
). Similarly, our post-hoc analyses excluding the 1/16 BD participants with type II BD (rather than type I), confirmed our primary result. However, further work to explore how BD subtypes differ in the brain/behavior interactions underlying reversal learning is warranted. In addition, while all of our participants were euthymic by the definition of having CDRS scores < 40 and YMRS scores < 12, we cannot rule out the possibility that subsyndromal mood symptoms were nonetheless present and impacted on our findings (84
). However, the lack of significant correlations between neural activation during reversal and YMRS or CDRS scores suggests that subsyndromal mood effects are less likely. Moreover, since the K-SADS was administered at enrollment and not at scan day, we cannot say for certain that BD participants did or did not meet K-SADS mania or depressive episode criteria on the scan day; however, it is highly unlikely given their mood (YMRS, CDRS) scores.
With respect to medications, most of our BD participants (13/16) were taking a combination of psychotropic medications, with no single agent predominating. To begin addressing the potential confound of medications on our results, we conducted exploratory analyses of those BD youth taking either atypical antipsychotic or anticonvulsant medications compared to those not, since 50% of the BD participants were taking either medication. Such analyses failed to show any difference in group-by-phase neural activation among BD youth based on either medication category. Recent evidence suggests that medication may bias toward type II, rather than type I, error (86
). Also, given the variety of our patients’ medication regimens, it is unlikely that medications would account for the consistent and relatively specific findings that we observed. Nevertheless, additional studies that pair treatment and neuroimaging in their design are needed to examine whether pharmacotherapy can reverse the cognitive flexibility deficits present in BD and, if so, the neural mechanisms that might account for this effect.
A final potential limitation is the age range of our participants. Specifically, we recruited pediatric BD and control participants across a broad age range during which a considerable amount of neural development occurs. For example, longitudinal structural neuroimaging studies have demonstrated the dynamic changes in PFC as children develop into adolescents and young adults (87
). Additionally, comparing cross-sectional and longitudinal fMRI data using a target detection task has shown a developmental shift from focal to diffuse PFC activation (88
). In the present study whereby BD and control groups were matched for age, secondary analyses do not show developmental effects as evidenced by no significant age or Tanner pubertal stage correlations. Nevertheless, the sample is too small to fully examine developmental effects, and it is likely that development may impact the brain/behavior interactions underlying reversal learning. Larger studies, with sufficient power to examine age effects, would thus likely be of interest from both clinical and research perspectives.