Our results show that, relative to HC subjects, children and adolescents with BD demonstrate increased DLPFC activation in the presence of comparable performance during the Go/NoGo task. At the behavioral level, BD subjects had more inaccurate Go trials (lower Go% correct), which may be due to impairments in sustained attention (Aron et al. 2004
), and lower d
-prime scores, which may indicate difficulty discriminating and appropriately responding to targets and nontargets (Wickens 2002
). Analysis of reaction times or errors in omission or commission did not indicate significant performance differences between the groups. This suggests that subjects from both groups were able to perform the inhibitory control task adequately at the presented level of difficulty.
Taken together, these results are consistent with the view that excessive recruitment of the right prefrontal cortex by the BD group during NoGo blocks may represent a mechanism for improving behavioral performance during response inhibition. Furthermore, our results support previous behavioral studies, suggesting that problems in sustained attention may represent a trait deficit of BD (Clark and Goodwin 2004
; Doyle et al. 2005
; Fleck et al. 2005
). Despite the discrepancy in Go trial behavioral performance, there were no significant between-group activation differences for the Go versus Rest contrast. This finding may indicate that, unlike the increased DLPFC activation observed for NoGo blocks, BD subjects were not able to neurally compensate for intrinsic deficits in sustained attention. Selective increase in DLPFC activation during NoGo blocks in the BD group may have resulted from the subjects' deliberate attempt to comply with the experimental focus on inhibiting inappropriate responses, as opposed to regulating more automatized behavior such as that required for Go blocks.
Our results are partially consistent with previous fMRI investigations that have reported abnormalities in prefrontal circuitry in pediatric BD (Blumberg et al. 2003b
; Chang et al. 2004
; Leibenluft et al. 2007
). While performing a color-naming Stroop task, 10 adolescents with BD, relative to controls, demonstrated increased activation in subcortical regions, including the putamen and thalamus, relative to prefrontal areas, suggesting a developmental disturbance in prefrontal functioning (Blumberg et al. 2003b
). In a study of twelve 9- to 18-year-old males with BD, BD subjects showed greater left DLPFC activation compared to controls during a visuospatial working memory task, and greater bilateral DLPFC activation while viewing negative relative to neutral-valenced pictures (Chang et al. 2004
). Some (n
10) among this cohort also performed the Go/NoGo task, and their results are presented in our study. Taken together, these studies suggest prefrontal dysfunction in pediatric BD across a variety of tasks, but are in contrast to the recent finding of increased frontostriatal activation in healthy controls relative to BD subjects during a stop signal task (Leibenluft et al. 2007
In contrast to prior studies, our findings suggest an atypical pattern of dorsal prefrontal activation in BD while achieving behavioral performance comparable to healthy controls. Alternatively, increased DLPFC activation in the BD group may be generally associated with greater neural effort needed to perform the cognitive task (MacDonald et al. 2000
; Compton et al. 2003
) compared to the HC group. Differences in the tasks, behavioral conditions, statistical contrasts employed, sample sizes, demographics, and clinical status across studies may all contribute to the variable results. For example, the lack of findings in the striatum in our current study may be attributable to the use of a simple design that may not have featured complex cognitive processes mediated by the striatum. Nevertheless, consistent with previous findings alluding to abnormalities in prefrontal circuitry in BD, the prefrontal activation profile in the presence study may be associated with emotional and attentional dysregulation in BD youth.
Some studies in adults with BD have suggested mood state-dependent changes in subcortical neural activation during simple motor tasks (Caligiuri et al. 2003
; Caligiuri et al. 2006
; Lohr and Caligiuri 2006
). On the basis of mood symptom ratings, our BD group, on average, had mild severity of manic symptoms (mean YMRS score
15.6) and symptoms commensurate with a depressed state (mean CDRS score
44.1). However, neither mania nor depression symptom severity was correlated with any task-related behavioral measures or brain activation within the BD group, suggesting that prefrontal overactivation observed in the BD group during this task may be independent of a current mood state. This lack of correlation between mood state and fMRI activation is supported by other studies performed in BD subjects during periods of euthymia (Strakowski et al. 2004
), and longitudinal studies in which frontostriatal activations remain consistent across several mood states (Marchand et al. 2007
Alhough we did not observe any indication that mood state affected our primary results, previous studies from our group and others suggest that increased prefrontal activation in subjects with mood dysregulation may be a sign of increased cortical control over a hyperactive limbic system (Mayberg 1997
; Chang et al. 2004
; Phillips and Vieta 2007
; Pavuluri et al. 2008
). There may be several possible reasons why we did not observe limbic hyperactivation in this study. First, our task was not designed to target amygdalar activation specifically. Nevertheless, it is possible that prefrontal structures may have successfully suppressed any task independent limbic hyperactivation in the BD group, even in the presence of mild to moderate hypomanic and depressive symptomatology. Alternatively, functional differences in limbic structures may only be present during active (Foland et al. 2008
) or prolonged symptoms of mania. In support of the latter hypothesis, bipolar adults who have a longer course of manic symptoms show patterns of limbic hyperactivity (Wessa et al. 2007
) and diminished prefrontal activity (Malhi et al. 2007
) while performing both cognitively and emotionally relevant fMRI tasks.
The co-occurrence of ADHD may be important when attempting to interpret behavioral and neural correlates of response inhibition in BD (Henin et al. 2007
). In our study, most (81%) BD subjects met criteria for ADHD and had high overall raw and standardized Conners' scores. Given the preponderance of ADHD symptoms in our sample, it is surprising that our results did not show reductions in frontostriatal activation during tasks of cognitive control as demonstrated in populations with ADHD only (Durston et al. 2003
; Rubia et al. 2005
; Vaidya et al. 2005
). Other studies have also shown increased activation in the ventrolateral prefrontal cortex during interference control and response competition in ADHD (Schulz et al. 2005
To address this issue directly, we would need to have had more equal proportions of BD subgroups with and without ADHD and have an additional comparison group comprised of children with just ADHD of comparable severity to our BD group. Although there were no significant correlations between ADHD symptom severity as measured by Conners' scores and task-related behavioral measures, brainstem activation in the level of the pons was positively correlated with higher (more severe) Conners' scores after adjusting for age, suggesting activation of regions other than frontostriatal networks previously examined in similar co-morbid populations (Adler et al. 2005
; Leibenluft et al. 2007
). Increased pontine activation could facilitate a compensatory level of alertness in the BD group to permit more accurate or control level behavioral performance on Go and NoGo epochs. Feasibility of brainstem fMRI activation has been demonstrated (Komisaruk et al. 2002
; Campbell et al. 2007
), but further investigation of this finding in pediatric populations is warranted. Moreover, more precise measures of ADHD symptom severity than the parent-reported Conners' rating scale may be needed to confirm the relationship between brain activation and symptom severity.
The NoGo−Go contrast employed in this study is associated with several cognitive processes and component functions of response inhibition, including sustained attention, target detection, and rule maintenance (Aron and Poldrack 2005
). We chose a block design to examine a combination of these processes over a sustained period of time to capitalize on a higher proportion of NoGo trials represented as compared to those generated by an event-related analysis. Although event-related designs and analyses might be able to extract individual cognitive processes subserved by activated brain regions (e.g., differentiating neural processes occurring during failed versus successful NoGo trials), they generate a lower proportion of NoGo trials than a block design and are extremely difficult for children with serious mood disorders to perform.
Moreover, in the context of high individual variances due to complex clinical heterogeneity from psychiatric disorders co-occurring with BD such as ADHD, a block design approach was preferred over an event-related design. This approach has been successfully used in typically developing children (Tamm et al. 2002
) and those with posttraumatic stress symptoms (Carrion et al. 2008
), fragile X (Hoeft et al. 2007
), and ADHD (Epstein et al. 2007b
). Using this method, the neural result of dorsolateral prefrontal overactivation in BD compared with HC is of particular importance because high cortical cognitive areas may be vulnerable to neurodegeneration and dysfunction with progression of bipolar illness (Chang 2007
There are a few limitations to this study, including prior and current history of medication exposure in the BD group and a lack of an ADHD-only comparison group. The generalizability of our results and our ability to detect some functional group differences may have been limited by interindividual differences in mood states and cognitive strategies employed to optimize task performance. Exposure of our subjects to psychotropic medications represents another potential confound. However, due to ethical and practical considerations, it is difficult to perform MRI studies on unmedicated children with BD. Exploratory analyses suggested that there may be general effects of medication exposure on brain activation in BD subjects, although the group sizes for these analyses were quite small and the length of exposure and number of medications variable. This suggests the possibility of type I and II errors, as has been described in previous studies examining medication effects on fMRI results (Leibenluft et al. 2007
Thus, the results of the medication analyses should be interpreted with caution and viewed as preliminary and hypothesis generating. For multiple reasons, including the co-occurrence of ADHD symptoms (Epstein et al. 2007a
), the BD group had high potential for motion, which necessitated the use of a mock scanner training protocol prior to the scan and applying a motion correction algorithm during postprocessing procedures. Behavioral or functional subgroup analyses on BD subjects based on motion severity were not possible due to the small sample size, but task-correlated motion was not significantly different across the BD and HC groups. Future studies examining larger samples would permit additional subgroup analyses relating bipolar symptoms to cognitive performance on executive functioning tasks.