The role of amygdala-prefrontal cortical circuitry in processing and regulating emotional information has been documented, with specific patterns of abnormal functioning reported mainly in BP-I.6, 10, 34
To our knowledge, this is the first study to examine whether BP-I and BP-NOS youth show similar patterns of abnormal activity in, and connectivity between, neural regions supporting emotion processing and regulation. We hypothesized that both BP-I and BP-NOS, relative to HC youth, would show significantly elevated amygdala and reduced VMPFC/VLPFC and DLPFC activity to emotional faces but that this pattern of neural activity would be attenuated in BP-NOS relative to that shown by BP-I youth(versus HC). Furthermore, we hypothesized reduced VMPFC-amygdala connectivity to emotional faces in both BP-I and BP-NOS youth (versus HC).
Our findings partially support our hypotheses. That is, BP-I youth versus HC did show elevated activity in key emotion processing and regulation regions to happy faces and reduced DLPFC activity to fearful faces. This pattern was not observed, however, in BP-NOS versus HC. Rather they showed reduced prefrontal cortical activity to neutral faces versus HC. Moreover, BP-I versus HC showed reduced VMPFC-amygdala coupling to fearful faces, which was not observed in BP-NOS. Rather, BP-NOS exhibited greater VMPFC-DLPFC coupling to happy faces versus HC and BP-I youth. Together, these findings suggest that, relative to healthy controls, BP-I and BP-NOS youth exhibit different patterns of neural activation and connectivity when processing emotional facial expressions.
In order to better understand these differential patterns of abnormal activation and connectivity in BP-NOS youth relative to BP-I youth, we first discuss findings in BP-I youth in relation to the extant neuroimaging literature in BP-I youth. Our findings of elevated amygdala and VMPFC activity to happy faces and reduced DLPFC to fearful faces in BP-I versus HC youth are consistent with results from previous studies using the same gender labeling task in BP-I adults.28, 35
Elevated amygdala activity to happy faces may reflect greater attentional bias and associated appraisal while elevated VMPFC activity may index greater implicit regulation of emotional responses toward these positive emotional stimuli in BP-I youth.5, 16
Although we did not replicate previous findings of elevated amygdala activity to fearful faces in BP-I youth versus HC,6, 9
we did replicate previous findings of reduced DLPFC to fearful faces reported in adult bipolar patients.35
Such reduction in DLPFC activity to fearful faces in BP-I youth may reflect reduced orienting to these negative emotional stimuli in bipolar individuals, as there is evidence to suggest that, during emotion processing, the orienting of attention toward emotional stimuli places demands on DLPFC.36
The pattern of elevated, rather than reduced, DLPFC activity to happy faces in BP-I youth in the present study may therefore reflect greater recruitment of orienting-related attentional and effortful regulatory resources in BP-I youth versus HC. Our findings in BP-I youth are also largely consistent with findings from the few extant studies in BP-I youth that reported abnormally elevated amygdala and prefrontal cortical activity to happy or positive emotional stimuli, and abnormally reduced DLPFC activity to threat-related stimuli. In particular, our findings of elevated amygdala activity to happy faces are consistent with recent findings of elevated amygdala activity during gender labeling of happy faces in BP-I youth versus HC9
and passive viewing of happy and angry faces in euthymic BP-I youth versus HC.7
With regard to connectivity, BP-I youth displayed reduced connectivity versus HC between VMPFC and left amygdala to fearful faces. Few studies have examined amygdala-prefrontal connectivity in pediatric bipolar disorder. The only study, to our knowledge, reported reduced connectivity between left amygdala and cortical association regions in BP-I youth versus HC to neutral faces subjectively rated as threatening.13
Given the role of VMPFC in modulating amygdala activity, our findings of reduced VMPFC-amygdala connectivity to fearful faces may be associated with altered functional maturation of the VMPFC in BP-I youth.37
The major findings in BP-NOS youth from the current study were unexpected. The neural activation findings suggest that BP-NOS youth exhibit reduced prefrontal cortical activation compared with HC to neutral faces when these faces are presented in the context of emotional faces (i.e. happy and fearful faces). There was, however, a trend effect suggesting that BP-NOS youth did exhibit, similar to BP-I youth versus HC, greater VMPFC activity to happy faces than HC. With regard to findings associated with neutral faces, there is evidence to suggest that emotional context can affect perception of, and neural activity to, neutral faces36
. Reductions in DLPFC activity to neutral faces in each of the two experiments (and in VMPFC to neutral faces in the happy experiment) in BP-NOS relative to HC, and reduced amygdala, VMPFC and DLPFC activity to neutral faces (in the happy experiment) in BP-NOS relative to BP-I, may therefore suggest that BP-NOS youth perceived neutral faces as less salient in the context of emotional faces such as happy or fearful facial expressions, than did HC or BP-I, but this requires further study. Taken together, neuroimaging findings to happy faces in BP-NOS relative to BP-I and HC indicate that BP-NOS may represent an “intermediate” state between being healthy and having BP-I. The reduced activity in prefrontal cortical regions, and prefrontal cortical regions and amygdala, to neutral faces presented in the happy experiment, in BP-NOS versus HC and BP-I, respectively, could represent a potential biological mechanism that prevents BP-NOS youth from developing more severe symptoms of bipolar disorder. Given the paucity of neuroimaging research in BP-NOS youth, however, these interpretations remain speculative.
With regard to functional connectivity, BP-NOS youth compared with HC exhibited greater
VMPFC-DLPFC coupling while viewing happy faces. According to animal models and recent neuroimaging studies, the DLPFC plays an indirect role in modulating the amygdala through connections via the VMPFC.5, 38
Thus, it is possible that greater VMPFC-DLPFC coupling in BP-NOS youth may explain why there was a trend for elevated VMPFC and DLPFC activity, but reduced amygdala activity, to happy faces in BP-NOS versus HC. Greater VMPFC-DLPFC coupling to happy faces in BP-NOS youth may therefore reflect enhanced recruitment of cognitive control resources during modulation of attention to perform the gender labeling task with happy faces, and is consistent with findings from a recent study demonstrating greater DLPFC activation during incidental versus direct processing of happy faces in euthymic BP-I youth versus HC.34
Our exploratory correlational analyses indicated that VMPFC-DLPFC coupling to happy faces was greater in BP-NOS youth with more severe depressive symptoms at the time of the scan. Such findings may be interpreted as suggesting that depressed BP-NOS youth may need to recruit more attentional resources when processing mood incongruent positive stimuli such as happy faces, but this should be the focus of future studies.
The fact that the BP-NOS youth did not exhibit reduced VMPFC-amygdala connectivity to fearful faces compared with HC suggests that, unlike BP-I youth, functioning of these regulatory systems may be less affected in BP-NOS youth. It is possible that, like BP-I youth, BP-NOS youth may tend toward having elevated neural activity to emotional stimuli but that such activity is dampened by compensatory patterns of activity such as greater coupling in regulatory systems, as shown with happy faces. Such compensatory patterns in BP-NOS youth may not be observed in contexts that do not elicit elevated neural responses in BP-NOS youth, for example, fearful faces. Previous findings in adult BP-I do, for example, indicate elevated amygdala and striatal activity to happy faces more than to fearful faces.16, 35
As such, there may be less need for recruitment of DLPFC regulatory circuitry in either youth patient group in the present study to fearful relative to happy faces. Our findings would then suggest that while BP-I youth adopted an inefficient strategy (given the presence of elevated amygdala activity to happy faces in BP-I youth) of activating DLPFC to happy faces, BP-NOS youth adopted a preferable strategy (given the absence of elevated amygdala activity in BP-NOS youth to these faces) of recruiting VMPFC-DLPFC connectivity. These differential patterns of connectivity in BP-I and BP-NOS youth relative to HC youth suggest that these groups do not share the same profile of alterations in the functioning of neural systems implicated in emotion processing and regulation. Further research is needed to better understand associations between such differential patterns and clinical presentation of bipolar disorder in youth.
Exploratory whole-brain analyses supported some of the ROI findings, particularly with regard to prefrontal cortical regions, as well as findings from emotional face processing neuroimaging studies.17
In particular, the group by emotion condition interaction for both the happy and fearful face tasks showed VMPFC activation. Other regions implicated in this interaction were the cerebellum, temporal cortex, and visual cortical regions. Although there were no significant findings in the amygdala in any of the whole-brain interactions, findings from these analyses did indicate recruitment of temporal regions, which are implicated in emotional information processing.17
Further, results from the post hoc analyses following the significant group by condition interactions generally supported ROI analyses of reduced prefrontal cortical activation to neutral faces in BP-NOS youth and to fearful faces in BP-I youth relative to healthy controls In contrast to our ROI findings yielding mostly bilateral findings, however, whole-brain analyses for the group by emotion condition interaction suggested a certain degree of laterality with mostly right hemispheric activation for the happy face task and left hemispheric activation for the fearful face condition. Findings from meta-analyses suggest that emotional face processing typically recruits bilateral prefrontal-subcortical regions.39
There is, however, evidence of valence-specific lateralization of brain response during negative emotion processing, particularly in left amygdala.39
Given the exploratory nature of our whole-brain analyses, these findings pertaining to laterality associated with emotional face processing in BP-NOS should be considered preliminary, and would require further study.
Certain limitations merit consideration. First, most BP-I and BP-NOS youths were medicated, which prevented us from comparing unmedicated BP-I and BP-NOS youth to HC. However, prior work suggests that medications may reduce group differences in activation.40
Second, there was no emotion labeling task to account for the possible deficits in emotion labeling in BP-I youth, given recent findings suggesting emotional face processing deficits in BP-I youth.41, 42
However, gender-labeling accuracy scores, which were included as covariates in the analyses, suggest that all youth attended to the stimuli equally well. Nevertheless, future studies should include an emotion labeling task either inside or outside of the scanner to investigate this issue further. Third, our sample size precluded the testing of a full group by emotion condition by hemisphere interaction. As such, PPI analyses were performed for each emotional face versus fixation separately. The valence specific group differences argue against a general face processing explanation of the functional connectivity analyses. Fourth, although differences in mood state between BP-I and BP-NOS could have impacted results, we did not find any significant group differences on mania or depression scores from interviews conducted at the time of the scan. However, high depression scores were positively correlated with VMPFC-DLPFC coupling in BP-NOS only suggesting that mood may have a differential role on emotion processing and regulation in this group and is an issue that requires further examinations.
This is the first study to demonstrate differential patterns of abnormal activity in, and connectivity between, amygdala-prefrontal cortical regions supporting emotion processing and regulation in youth with BP-I and BP-NOS versus HC. Our findings indicate that BP-I youth exhibit greater activation in corticolimbic regions to happy faces, reduced DLPFC activation to fearful faces, and prefrontal-amygdala disconnectivity to fearful faces, versus HC. BP-NOS youth, however, did not differ from HC when processing happy or fearful faces. Rather, they exhibited, compared to HC, reduced prefrontal activation to neutral faces along with greater VMPFC-DLPFC coupling to happy faces, which was positively associated with depressive symptoms. These differential patterns in BP-I and BP-NOS youth suggest that BP-NOS youth do not exhibit elevated reactivity to positive emotional stimuli versus HC perhaps because of greater prefrontal connectivity enabling them to modulate attention in such contexts. Future longitudinal studies are warranted to examine whether these differential patterns of abnormal activity and connectivity predict future onset of BP-I/II in BP-NOS youth.